Compounds for the treatment and prophylaxis of respiratory syncytial virus disease

ABSTRACT

A compound of formula (I)as well as pharmaceutically acceptable salt thereof, wherein R1 to R10, A, Q, X and Y are as defined in the specification and claims, and their use as a pharmaceutical for the treatment or prophylaxis of respiratory syncytial virus disease.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of International Patent ApplicationNos. PCT/CN2012/078439, filed Jul. 10, 2012 and PCT/CN2011/078258, filedAug. 11, 2011, which are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The invention relates to compounds which are respiratory syncytial virus(RSV) inhibitors and which are useful in the treatment or prophylaxis ofRSV disease.

BACKGROUND OF THE INVENTION

Respiratory Syncytial Virus (RSV) belongs to the family ofParamyxoviridae, subfamily of Pneumovirinae. The human RSV is a majorcause of acute upper and lower respiratory tract infection in infantsand children. Almost all children are infected by RSV at least once byage of three. Natural human immunity against RSV is incomplete. Innormal adults and older children, RSV infection is mainly associatedwith upper respiratory tract symptoms. Severe cases of RSV infectionoften lead to bronchiolitis and pneumonia, which requireshospitalization. High-risk factors for lower respiratory trackinfections include premature birth, congenital heart disease, chronicpulmonary disease, and immuno-compromised conditions. A severe infectionat young age may lead to recurrent wheezing and asthma. For the elderly,RSV-related mortality rate becomes higher with advancing age.

There is no RSV vaccine available for human use, despite of manyattempts in subunit vaccine and live-attenuated vaccine approaches.Virazole®, the aerosol form of ribavirin, is the only approved antiviraldrug for treatment of RSV infection. However, it is rarely usedclinically, due to limited efficacy and potential side effects. Twomarketed prophalyxis antibodies were developed by MedImmune (CA, USA).

RSV-IGIV (brand name RespiGam) is polyclonal-concentrated RSVneutralizing antibody administered through monthly infusion of 750 mg/kgin hospital (Wandstrat T L, Ann Pharmacother. 1997 January; 31(1):83-8).Subsequently, the usage of RSV-IGIV was largely replaced by palivizumab(brand name Synagis®), a humanized monoclonal antibody against RSVfusion (F) protein approved for prophylaxis in high-risk infants in1998. When administered intramuscularly at 15 mg/kg once a month for theduration of RSV season, palivizumab demonstrated 45-55% reduction ofhospitalization rate caused by RSV infection in selected infants(Pediatrics. 1998 September; 102(3):531-7; Feltes T F et al, J Pediatr.2003 October; 143(4):532-40). Unfortunately, palivizumab is noteffective in the treatment of established RSV infection. A newer versionmonoclonal antibody, motavizumab, was designed as potential replacementof palivizumab but failed to show additional benefit over palivizumab inrecent Phase III clinical trials (Feltes T F et al, Pediatr Res. 2011April 25, Epub ahead of print).

A number of small molecule RSV inhibitors have been discovered. Amongthem, only a few reached Phase I or II clinical trials. ArrowTherapeutics (now a group in AstraZeneca, UK) completed a five-yearPhase II trial of nucleocapsid (N) protein inhibitor RSV-604 in stemcell transplantation patients by February 2010 (www.clinicaltrials.gov),but has not released the final results. Most of other small moleculeswere put on hold for various reasons.

RNAi therapeutics against RSV have also been thoroughly studied.ALN-RSV01 (Alnylam Pharmaceuticals, MA, USA) is a siRNA targeting on RSVgene. A nasal spay administered for two days before and for three daysafter RSV inoculation decreased infection rate among adult volunteers(DeVincenzo J. et al, Proc Natl Acad Sci USA. 2010 May 11; 107 (19):8800-5). In another Phase II trial using naturally infected lungtransplantation patients, results were not sufficient for conclusion ofantiviral efficacy, though certain health benefits have been observed(Zamora M R et al, Am J Respir Crit Care Med. 2011 Feb. 15; 183(4):531-8). Additional Phase IIb clinical trials in similar patientpopulation for ALN-RSV01 are on-going (www.clinicaltrials.gov).

Nevertheless, safe and effective treatment for RSV disease is neededurgently.

SUMMARY OF THE INVENTION

The invention relates to compounds of formula (I)

and their use in pharmaceuticals for the treatment and prophylaxis ofRSV disease.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates in particular to compounds of formula (I)

Wherein

-   -   R¹ is hydrogen, halogen, or C₁₋₆alkyl;    -   R² is hydrogen, halogen, or C₁₋₆alkyl;    -   R³ is hydrogen, halogen, or C₁₋₆alkyl;    -   R⁴ is hydrogen, or C₁₋₆alkyl;    -   R⁵ is hydrogen, or halogen;    -   R⁶ is hydrogen, halogen, hydroxy, C₁₋₆alkoxy, carboxy,        morpholinyl, or 4-C₀₋₆alkylpiperazin-1-yl;    -   R⁷ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy,        C₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,        C₁₋₆alkylsulfonyl, phenoxy, or hydroxy(CH₂)₂₋₆—O—;    -   R⁸ is hydrogen, halogen, or C₁₋₆alkoxy;    -   R⁹ is hydrogen, C₁₋₆alkyl, or ═O;    -   R¹⁰ is hydrogen, or ═O, provided that R⁹ and R¹⁰ are not ═O        simultaneously;

-   A is nitrogen, or —C—R¹¹, wherein R¹¹ is hydrogen, halogen,    C₁₋₆alkyl, cycloalkyl, C₁₋₆alkoxy, trifluoromethyl,    trifluoromethoxy, pyridinyloxy, C₁₋₆alkoxy(CH₂)₁₋₆—O—,    difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl,    aminocarbonyl, hydroxy(CH₂)₂₋₆—O—, C₁₋₆alkylsulfinyl,    C₁₋₆alkylsulfonyl, hydroxy(CH₂)₁₋₆, deuteratedC₁₋₆alkyl, carboxyl,    C₁₋₆alkoxycarbonyl, hydroxy, difluoromethyl, —CH(hydroxy) C₁₋₆alkyl,    or C₁₋₆alkylsulfanyl;    -   X is —CH₂—, —O—, —NH—, —CF₂—, —C(C₁₋₆alkyl)(OH)—, —S—, —C(═O)—,        —C(═NOC₀₋₆alkyl)-, —S(═O)—, —S(O₂)— or —S(═O)(NH)—;    -   Y is —CH—, or nitrogen;    -   Q is hydrogen; halogen; C₁₋₆alkyl, unsubstituted or once or        twice substituted by amino or hydroxy, provided that        di-substitution is not on the same carbon;        amino(CH₂)₂₋₆aminosulfonyl;        2-amino-4,5-dihydro-1,3-oxazol-4-yl(CH₂)₁₋₆; carboxy(CH₂)₁₋₆;        phenylsulfonyl; piperidin-4-yl-carbonyl; 1H-pyrazol-3-yl;        pyrrolidin-3-yloxy; piperidin-4-yloxy; amino(CH₂)₂₋₆—O—; or        NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen, C₁₋₆alkyl, or        hydroxy(CH₂)₂₋₆;    -   and the other one is    -   {1-[amino(CH₂)₀₋₆]-3,3-difluorocyclobutyl}(CH₂)₁₋₆;        guanidino(CH₂)₂₋₆; (S—C₁₋₆alkylsulfonimidoyl)(CH₂)₂₋₆;        2-oxa-6-aza-spiro[3.4]oct-8-yl;        {3-[amino(CH₂)₀₋₆]tetrahydrofuran-3-yl}(CH₂)₁₋₆;        3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;        3-amino-1,1-dioxidothietan-3-ylmethyl;        3-(aminomethyl)thietan-3-ylmethyl;        (1,1-dioxidothiomorpholin-4-yl)ethyl;        C₀₋₆alkyl(oxetanyl)N(CH₂)₂₋₆; 4,5-dihydro-1H-imidazol-2-yl;        amino(CH₂)₂₋₆—O—(CH₂)₂₋₆; amino(CH₂)₂₋₁₀;        amino(CH₂)₁₋₆difluoromethyl(CH₂)₁₋₆;        amino(CH₂)₁₋₆difluoromethyldifluoromethyl(CH₂)₁₋₆;        amino(CH₂)₁₋₆fluoromethyl(CH₂)₁₋₆;        amino(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆; amino(CH₂)₀₋₆oxetanyl(CH₂)₁₋₆;        amino(CH₂)₂₋₆sulfanyl(CH₂)₂₋₆; amino(CH₂)₂₋₆sulfonyl(CH₂)₂₋₆;        amino(CH₂)₀₋₆carbonyl(CH₂)₀₋₆; aminocycloalkyl(CH₂)₀₋₆;        2-aminodihydrooxazol-4-yl(CH₂)₁₋₆;        2-aminodihydrooxazol-5-yl(CH₂)₁₋₆;        (2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl;        aminophenyl; 4-aminotetrahydropyran-4-yl(CH₂)₁₋₆;        azetidin-2-yl(CH₂)₁₋₆; azetidin-3-yl(CH₂)₀₋₆;        azetidinylcarbonyl; C₁₋₆alkoxy(CH₂)₂₋₆;        C₁₋₆alkoxy(CH₂)₂₋₆amino(CH₂)₂₋₆; C₁₋₆alkyl;        C₁₋₆alkylamino(CH₂)₂₋₆; C₁₋₆alkylaminocarbonyl(CH₂)₀₋₆;        C₁₋₆alkylaminooxetanyl(CH₂)₁₋₆; C₁₋₆alkylcarbonyl;        C₁₋₆alkylcarbonylamino(CH₂)₂₋₆;        C₁₋₆alkylcarbonylamino(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆;        C₁₋₆alkylsulfinyl(CH₂)₂₋₆; C₁₋₆alkylsulfonyl; carboxy(CH₂)₁₋₆;        cyano(CH₂)₁₋₆; diC₁₋₆alkylamino(CH₂)₂₋₆; diC₁₋₆        alkylaminocarbonyl; difluoromethyl(CH₂)₁₋₆amino(CH₂)₂₋₆;        hydrogen; hydroxy(CH₂)₂₋₁₀; hydroxy(CH₂)₂₋₆amino(CH₂)₂₋₆;        hydroxy(CH₂)₁₋₆carbonyl; hydroxy(CH₂)₀₋₆oxetanyl(CH₂)₁₋₆;        hydroxy(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆; hydroxycycloalkyl; isoxazolyl;        morpholin-2-yl(CH₂)₁₋₆; morpholin-4-yl(CH₂)₂₋₆;        oxetanyl(CH₂)₀₋₆; N-oxetanylpyrrolidin-3-yl;        oxo-pyrrolidinylcarbonyl; phenylaminocarbonyl;        phenyl(CH₂)₀₋₆aminooxetanyl(CH₂)₁₋₆, phenylcarbonyl;        piperazinyl(CH₂)₂₋₆; piperidin-1-yl(CH₂)₂₋₆;        piperidin-2-yl(CH₂)₁₋₆; piperidin-3-yl(CH₂)₀₋₆;        piperidin-4-yl(CH₂)₀₋₆; piperidinylcarbonyl; pyrazinylcarbonyl;        pyrazol-3-yl; pyridazinylcarbonyl; pyridinyl(CH₂)₀₋₆carbonyl;        pyridinylamino(CH₂)₂₋₆; pyrrolidin-3-yl, unsubstituted or        4-substituted by halogen; pyrrolidin-4-yl, unsubstituted or        3-substituted by hydroxy or C₁₋₆alkoxy; pyrrolidin-2-yl(CH₂)₁₋₆;        pyrrolidinylcarbonyl; tetrahydrofuran-3-yl;        tetrahydropyran-4-yl; tetrazolyl(CH₂)₂₋₆;        trifluoromethylcarbonylamino(CH₂)₁₋₆oxetanyl;        trifluoromethylsulfonyl;

-   -    wherein R¹⁴ is hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₁₋₆; R¹⁵ is        hydroxy, C₁₋₆alkyl, hydroxy(CH₂)₁₋₆ or amino; and R¹⁶ is        C₁₋₆alkyl, trifluoromethyl, hydroxy(CH₂)₁₋₆, amino(CH₂)₁₋₆,        aminocarboxy or carboxy(CH₂)₁₋₆;

-   -    wherein R¹⁷ is hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₁₋₆; R¹⁸ is        hydroxy(CH₂)₁₋₆ or C₁₋₆alkyl; R¹⁹ is hydroxy(CH₂)₁₋₆,        amino(CH₂)₁₋₆, carboxy or aminocarboxy(CH₂)₀₋₆; or

-   -    wherein R²⁰ is hydrogen or C₁₋₆alkyl; R²¹ is C₁₋₆alkyl; R²² is        C₁₋₆alkoxy or amino;    -   R¹² and R¹³, with the nitrogen atom to which they are attached,        may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl,        azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be        unsubstituted, once or twice substituted by a group selected        from halogen, C₁₋₆alkyl, C₁₋₆alkoxy, gemdimethyl, amino,        aminocarbonyl, hydroxy, oxetanylamino, C₁₋₆alkylpiperazinyl, and        amino(CH₂)₁₋₆;    -   R¹² and R¹³, with the nitrogen atom to which they are attached        may form a bridge ring or a spiral ring selected from        2-oxa-6-aza-spiro[3.4]octan-6-yl,        2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl,        (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,        4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-5-yl,        2-aza-bicyclo[2.1.1]hexan-2-yl, and        3-aza-bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or        further substituted by amino;    -   and pharmaceutically acceptable salt and stereoisomers thereof.

It has been found that the compounds of the present invention belong toa new chemical class of RSV inhibitors for the treatment or prophylaxisof RSV infection. The compounds of the invention are therefore useful inthe treatment or prophylaxis of RSV disease.

As used herein, the term “C₀₋₆alkyl” alone or in combination signifies achemical bond, or hydrogen, or saturated, linear- or branched chainalkyl group containing 1 to 6, preferably 1 to 4 carbon atoms, forexample methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, tert-butyland the like. Preferred “C₀₋₆alkyl” groups are chemical bond, hydrogen,methyl, ethyl, isopropyl, tert-butyl.

As used herein, the term “C₁₋₆alkyl” alone or in combination signifies asaturated, linear- or branched chain alkyl group containing 1 to 6,preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl,isopropyl, 1-butyl, 2-butyl, tert-butyl and the like. Preferred“C₁₋₆alkyl” groups are methyl, ethyl, isopropyl, tert-butyl.

As used herein, the term “C₂₋₆alkyl” alone or in combination signifies asaturated, linear- or branched chain alkyl group containing 2 to 6,preferably 2 to 4 carbon atoms, for example ethyl, propyl, isopropyl,1-butyl, 2-butyl, tert-butyl and the like. Preferred “C₂₋₆alkyl” groupsare ethyl, isopropyl, tert-butyl.

As used herein, the term “—(CH₂)₀₋₆—” signifies a chemical link,hydrogen, or a saturated, linear alkyl chain containing from 1 to 6carbon atoms, preferably, the term signifies hydrogen or —(CH₂)₁₋₄—.

As used herein, the term “—(CH₂)₁₋₆—” signifies a saturated, linearalkyl chain containing from 1 to 6 carbon atoms, preferably from 1 to 4carbon atoms.

As used herein, the term “—(CH₂)₂₋₆—” signifies a saturated, linearalkyl chain containing from 2 to 6 carbon atoms, preferably from 2 to 4carbon atoms.

As used herein, the term “—(CH₂)₂₋₁₀—” signifies a saturated, linearalkyl chain containing from 2 to 10 carbon atoms, preferably from 2 to 4carbon atoms.

The term “cycloalkyl”, alone or in combination, refers to a saturatedcarbon ring containing from 3 to 7 carbon atoms, preferably from 3 to 6carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and the like. Preferred cycloalkyl groups arecyclopropyl, cyclopentyl and cyclohexyl.

The term “C₁₋₆alkoxy” alone or in combination signifies a groupC₁₋₆alkyl-O—, wherein the “C₁₋₆alkyl” is as defined above; for examplemethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy,t-butoxy and the like. Preferred C₁₋₆alkoxy groups are methoxy andethoxy and more preferably methoxy.

The term “C₂₋₆alkoxy” alone or in combination signifies a groupC₂₋₆alkyl-O—, wherein the “C₂₋₆alkyl” is as defined above; for exampleethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy, t-butoxy andthe like. Preferred C₁₋₆alkoxy groups is ethoxy.

The term “halogen” means fluorine, chlorine, bromine or iodine. Halogenis preferably fluorine or chlorine.

The term “hydroxy” alone or in combination refers to the group —OH.

The term “carbonyl” alone or in combination refers to the group —C(O)—.

The term “carboxy” alone or in combination refers to the group —COOH.

The term “amino”, alone or in combination, refers to primary (—NH₂),secondary (—NH—) or tertiary amino

The term “sulfonyl” alone or in combination refers to the group —S(O)₂—.

The term “C₁₋₆alkylsulfanyl” alone or in combination refers to the group—S—C₁₋₆alkyl.

The term “C₁₋₆alkylsulfinyl” alone or in combination refers to the group—S(O)—C₁₋₆alkyl.

The term “oxetanyl” alone or in combination refers to the group

The compounds according to formula I does not include those in which thesp³ hybrid carbon atom is disubstituted by two nitrogen atoms, or onenitrogen atom and one oxygen atom simultaneously. The compoundsaccording to the present invention may exist in the form of theirpharmaceutically acceptable salts. The term “pharmaceutically acceptablesalt” refers to conventional acid-addition salts or base-addition saltsthat retain the biological effectiveness and properties of the compoundsof formula (I) and are formed from suitable non-toxic organic orinorganic acids or organic or inorganic bases. Acid-addition saltsinclude for example those derived from inorganic acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,sulfamic acid, phosphoric acid and nitric acid, and those derived fromorganic acids such as p-toluenesulfonic acid, salicylic acid,methanesulfonic acid, oxalic acid, succinic acid, citric acid, malicacid, lactic acid, fumaric acid, and the like. Base-addition saltsinclude those derived from ammonium, potassium, sodium and, quaternaryammonium hydroxides, such as for example, tetramethyl ammoniumhydroxide. The chemical modification of a pharmaceutical compound into asalt is a technique well known to pharmaceutical chemists in order toobtain improved physical and chemical stability, hygroscopicity,flowability and solubility of compounds. It is for example described inBastin R. J., et. al., Organic Process Research & Development 2000, 4,427-435; or in Ansel, H., et. al., In: Pharmaceutical Dosage Forms andDrug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Preferredare the sodium salts of the compounds of formula (I).

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as acetate, propionateand isobutyrate. Additionally, any physiologically acceptableequivalents of the compounds of general formula (I), similar to themetabolically labile esters, which are capable of producing the parentcompounds of general formula (I) in vivo, are within the scope of thisinvention. Preferred are the methyl and ethyl esters of the compounds offormula (I).

Compounds of the general formula (I) which contain one or several chiralcenters can either be present as racemates, diastereomeric mixtures, oroptically active single isomers. The racemates can be separatedaccording to known methods into the enantiomers. Preferably,diastereomeric salts which can be separated by crystallization areformed from the racemic mixtures by reaction with an optically activeacid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid,lactic acid or camphorsulfonic acid.

Another embodiment of present invention is (ii) a compound of formula(I) or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is hydrogen, halogen or C₁₋₆alkyl;    -   R² is hydrogen, halogen or C₁₋₆alkyl;    -   R³ is hydrogen, halogen or C₁₋₆alkyl;    -   R⁴ is hydrogen or C₁₋₆alkyl;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen, halogen, hydroxy, C₁₋₆ alkoxy, morpholinyl or        4-C₀₋₆alkylpiperazin-1-yl;    -   R⁷ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, phenoxy or        hydroxy(CH₂)₂₋₆—O—;    -   R⁸ is hydrogen, halogen or C₁₋₆alkoxy;    -   R⁹ is hydrogen or C₁₋₆alkyl;    -   R¹⁰ is hydrogen;

A is nitrogen or —C—R¹¹, wherein R¹¹ is hydrogen, halogen, C₁₋₆ alkyl,cycloalkyl, C₁₋₆alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy,C₁₋₆alkoxy(CH₂)₁₋₆—O—, difluoromethoxy, cyano, nitro, amino, vinyl,acetylenyl, aminocarbonyl, hydroxy(CH₂)₂₋₆—O—, C₁₋₆alkylsulfinyl,hydroxy(CH₂)₁₋₆, deuteratedC₁₋₆alkyl, carboxyl, alkoxycarbonyl, hydroxy,difluoromethyl, —CH(hydroxy)C₁₋₆alkyl or C₁₋₆alkylsulfanyl;

-   -   X is S, S═O, SO₂ or S(O)NH;    -   Y is —CH— or nitrogen;    -   Q is C₁₋₆alkyl, unsubstituted or once substituted by amino;        amino(CH₂)₂₋₆aminosulfonyl;        2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl; carboxy(CH₂)₁₋₆;        phenylsulfonyl; piperidin-4-yl-carbonyl; 1H-pyrazol-3-yl;        pyrrolidin-3-yloxy; piperidin-4-yloxy; amino(CH₂)₂₋₆—O—;        or    -   NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen, C₁₋₆alkyl or        hydroxy(CH₂)₂₋₆;    -   and the other one is    -   {1-[amino(CH₂)₀₋₆]-3,3-difluorocyclobutyl}(CH₂)₁₋₆; (S—C₁₋₆        alkylsulfonimidoyl)(CH₂)₂₋₆;    -   {3-[amino(CH₂)₀₋₆]tetrahydrofuran-3-yl}(CH₂)₁₋₆;        (2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl;        3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;        3-(aminomethyl)thietan-3-ylmethyl;        (1,1-dioxidothiomorpholin-4-yl)ethyl;        C₀₋₆alkyl(oxetanyl)N(CH₂)₂₋₆; 4,5-dihydro-1H-imidazol-2-yl;        amino(CH₂)₂₋₆—O—(CH₂)₂₋₆; amino(CH₂)₂₋₁₀;        amino(CH₂)₀₋₆carbonyl(CH₂)₀₋₆; amino(CH₂)₁₋₆        difluoromethyl(CH₂)₁₋₆; amino(CH₂)₁₋₆        difluoromethyldifluoromethyl(CH₂)₁₋₆;        amino(CH₂)₁₋₆fluoromethyl(CH₂)₁₋₆;        amino(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆; amino(CH₂)₀₋₆oxetanyl(CH₂)₁₋₆;        amino(CH₂)₂₋₆sulfanyl(CH₂)₂₋₆; amino(CH₂)₂₋₆sulfonyl(CH₂)₂₋₆;        1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl;        4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl;        1-aminocyclopropylethyl; 1-aminocyclopropylmethyl;        (2-amino-4,5-dihydro-oxazol-5-yl)(CH₂)₁₋₆;        (2-amino-4,5-dihydro-oxazol-4-yl)(CH₂)₁₋₆; aminophenyl;        4-aminotetrahydropyran-4-yl(CH₂)₁₋₆; azetidin-2-yl(CH₂)₁₋₆;        azetidin-3-yl(CH₂)₀₋₆; azetidin-3-ylcarbonyl;        C₁₋₆alkoxy(CH₂)₂₋₆; C₁₋₆alkoxy(CH₂)₂₋₆amino(CH₂)₂₋₆; C₁₋₆alkyl;        C₁₋₆alkylamino(CH₂)₂₋₆; C₁₋₆ alkylaminooxetanyl(CH₂)₁₋₆; C₁₋₆        alkylcarbonyl; C₁₋₆alkylaminocarbonyl(CH₂)₀₋₆; C₁₋₆        alkylcarbonylamino(CH₂)₂₋₆;        C₁₋₆alkylcarbonylamino(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆; C₁₋₆        alkylsulfinyl(CH₂)₂₋₆; C₁₋₆alkylsulfonyl; carboxy(CH₂)₁₋₆;        cyano(CH₂)₁₋₆; diC₁₋₆ alkylamino(CH₂)₂₋₆; diC₁₋₆        alkylaminocarbonyl; difluoromethyl(CH₂)₁₋₆ amino(CH₂)₂₋₆;        hydrogen; hydroxy(CH₂)₂₋₁₀; hydroxy(CH₂)₂₋₆amino(CH₂)₂₋₆;        hydroxy(CH₂)₁₋₆carbonyl; hydroxy(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆;        hydroxy(CH₂)₀₋₆oxetanyl(CH₂)₁₋₆; 4-hydroxycyclohexyl;        isoxazol-3-yl; morpholin-2-yl(CH₂)₁₋₆; morpholin-4-yl(CH₂)₂₋₆;        2-oxa-6-aza-spiro[3.4]oct-8-yl; oxetanyl(CH₂)₀₋₆;        N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidinylcarbonyl;        phenylaminocarbonyl; phenyl(CH₂)₀₋₆aminooxetanyl(CH₂)₁₋₆,        phenylcarbonyl; piperazinyl(CH₂)₂₋₆; piperidin-1-yl(CH₂)₂₋₆;        piperidin-2-yl(CH₂)₁₋₆; piperidin-3-yl(CH₂)₀₋₆;        piperidin-4-yl(CH₂)₀₋₆; piperidinylcarbonyl; pyrazinylcarbonyl;        pyrazol-3-yl; pyridazinylcarbonyl; pyridinyl(CH₂)₀₋₆carbonyl;        pyridinylamino(CH₂)₂₋₆; pyrrolidin-3-yl, unsubstituted or        4-substituted by halogen; pyrrolidin-4-yl, unsubstituted or        3-substituted by hydroxy or C₁₋₆alkoxy; pyrrolidin-2-yl(CH₂)₁₋₆;        pyrrolidinylcarbonyl; tetrahydrofuran-3-yl;        tetrahydropyran-4-yl; tetrazolyl(CH₂)₂₋₆;        trifluoromethylcarbonylamino(CH₂)₁₋₆oxetanyl;        trifluoromethylsulfonyl;

-   -    wherein R¹⁴ is hydrogen or C₁₋₆alkyl; R¹⁵ is hydroxy, C₁₋₆alkyl        or amino; and R¹⁶ is C₁₋₆alkyl, trifluoromethyl,        hydroxy(CH₂)₁₋₆, amino(CH₂)₁₋₆, aminocarbonyl or        carboxy(CH₂)₁₋₆;

-   -    wherein R¹⁷ is hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₁₋₆; R¹⁸ is        hydroxy(CH₂)₁₋₆ or C₁₋₆alkyl; R¹⁹ is hydroxy(CH₂)₁₋₆,        amino(CH₂)₁₋₆, carboxy or aminocarbonyl(CH₂)₀₋₆; or

-   -    wherein R²⁰ is hydrogen or C₁₋₆alkyl; R²¹ is C₁₋₆alkyl; R²² is        C₁₋₆alkoxy or amino;    -   R¹² and R¹³, with the nitrogen atom to which they are attached,        may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl,        azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be        unsubstituted, once or twice substituted by a group selected        from halogen, C₁₋₆alkyl, C₁₋₆alkoxy, gemdimethyl, amino,        aminocarbonyl, hydroxy, oxetanylamino, C₁₋₆alkylpiperazinyl, and        amino(CH₂)₁₋₆;    -   R¹² and R¹³, with the nitrogen atom to which they are may form a        bridge ring or a spiral ring selected from        2-oxa-6-aza-spiro[3.4]octan-6-yl,        2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl,        (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,        4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-5-yl,        2-aza-bicyclo[2.1.1]hexan-2-yl and        3-aza-bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or        further substituted by amino.

Further embodiment of present invention is (iii) a compound of formula(I) or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹, R² or R³ are hydrogen, fluoro, chloro or methyl;    -   R⁴ is hydrogen or methyl;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen, fluoro, hydroxy, methoxy, morpholinyl or        4-(propan-2-yl)piperazin-1-yl;    -   R⁷ is hydrogen, fluoro, chloro, methyl, methoxy, ethoxy,        hydroxyethoxy or phenoxy;    -   R⁸ is hydrogen, fluoro or methoxy;    -   R⁹ is hydrogen or methyl;    -   R¹⁰ is hydrogen;

-   A is nitrogen or —C—R¹¹, wherein R¹¹ is hydrogen, fluoro, chloro,    bromo, methyl, ethyl, cyclopropyl, methoxy, trifluoromethyl,    trifluoromethoxy, pyridinyloxy, methoxyethoxy, difluoromethoxy,    cyano, nitro, amino, vinyl, acetylenyl, aminocarbonyl,    hydroxyethoxy, methylsulfanyl, methylsulfinyl, hydroxymethyl,    deuteratedmethyl, carboxyl, methoxycarbonyl, hydroxy,    difluoromethyl, methylCH(hydroxy)- or methylsulfonyl;    -   X is S, S═O, SO₂ or S(O)NH;    -   Y is —CH— or nitrogen;    -   Q is 2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl; aminoethoxy;        aminoethylaminosulfonyl; aminopropyl; carboxyethyl; methyl;        phenylsulfonyl; piperidin-4-yl-carbonyl; piperidin-4-yloxy;        1H-pyrazol-3-yl; pyrrolidin-3-yloxy; or NR¹²R¹³, wherein one of        R¹² and R¹³ is hydrogen, methyl or hydroxyethyl; and the other        one is aminobutyl; aminocarbonylethyl; aminocarbonylmethyl;        1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl;        4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl;        1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; aminodecyl;        (2-amino-4,5-dihydro-oxazol-5-yl)methyl;        (2-amino-4,5-dihydro-oxazol-4-yl)methyl; aminoethoxyethyl;        aminoethyl; aminoethylcarbonyl; amino ethylfluoromethylmethyl;        amino ethylsulfanylethyl; aminoethylsulfonylethyl; aminoheptyl;        aminohexyl; aminomethylcarbonyl;        (1-aminomethyl-3,3-difluorocyclobutyl)methyl;        aminomethyldifluoromethyldifluoromethylmethyl;        aminomethyldifluoromethylmethyl;        (2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl;        3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;        aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl;        aminomethyloxetanyl; aminomethyloxetanylmethyl;        3-(aminomethyl)thietan-3-ylmethyl; aminononyl; aminooctyl;        aminooxetanylethyl; aminooxetanylmethyl; aminopentyl;        aminophenyl; aminopropyl; 4-aminotetrahydropyran-4-ylmethyl;        3-aminotetrahydrofuran-3-ylmethyl; azetidin-3-yl;        azetidin-3-ylcarbonyl; azetidin-2-ylmethyl; azetidin-3-ylmethyl;        carboxyethyl; carboxymethyl; cyanoethyl;        difluoromethylmethylaminoethyl; 4,5-dihydro-1H-imidazol-2-yl;        dimethylaminocarbonyl; dimethylaminoethyl;        (1,1-dioxidothiomorpholin-4-yl)ethyl; ethyl; ethylaminocarbonyl;        ethylaminoethyl; ethylaminooxetanylmethyl; ethyl        (oxetanyl)aminoethyl; hydrogen; 4-hydroxycyclohexyl;        hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl;        hydroxymethylcarbonyl; hydroxymethyloxetanylmethyl;        hydroxynonyl; hydroxypropyl; isoxazol-3-yl; methoxyethyl;        methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl;        methylaminoethyl; methylcarbonyl; methylcarbonylaminoethyl;        methylcarbonylaminomethyloxetanylmethyl;        methylcarbonylaminopropyl; methylsulfinylethyl;        2-(S-methylsulfonimidoyl)ethyl; methylsulfonyl;        morpholin-4-ylethyl; morpholin-2-ylmethyl;        2-oxa-6-aza-spiro[3.4]oct-8-yl; oxetanyl; oxetanylaminoethyl;        oxetanylaminopropyl; oxetanylmethyl; N-oxetanylpyrrolidin-3-yl;        oxo-pyrrolidin-4-ylcarbonyl; phenylaminocarbonyl;        phenylcarbonyl; phenylmethylaminooxetanylmethyl;        piperazin-1-ylethyl; piperidin-2-ylcarbonyl;        piperidin-3-ylcarbonyl; piperidin-4-ylcarbonyl; piperidin-3-yl;        piperidin-4-yl; piperidin-1-ylethyl; piperidin-2-ylmethyl;        pyrazin-2-ylcarbonyl; pyrazol-3-yl; pyridazin-3-ylcarbonyl;        pyridine-2-ylmethylcarbonyl; pyridine-2-ylaminoethyl;        pyridine-2-ylcarbonyl; pyridine-3-ylcarbonyl; pyrrolidin-3-yl,        unsubstituted or 4-substituted by fluoro; pyrrolidin-4-yl,        unsubstituted or 3-substituted by hydroxy or methoxy;        pyrrolidin-2-ylmethyl; pyrrolidin-2-ylcarbonyl;        tetrahydrofuran-3-yl; tetrahydropyran-4-yl; tetrazolylethyl;        trifluoromethylsulfonyl;        trifluoromethylcarbonylaminomethyloxetanyl;

-   -   wherein R¹⁴ is hydrogen or methyl; R¹⁵ is hydroxy, methyl or        amino; and R¹⁶ is methyl, trifluoromethyl, hydroxymethyl,        hydroxyethyl, aminomethyl, aminocarbonyl or carboxymethyl;

-   -   wherein R¹⁷ is hydrogen, methyl or hydroxymethyl; R¹⁸ is        hydroxymethyl or methyl; R¹⁹ is hydroxymethyl, aminomethyl,        carboxy, aminocarbonyl or aminocarbonylmethyl;    -   or

-   -    wherein R²⁰ is hydrogen or methyl; R²¹ is methyl or ethyl; R²²        is methoxy or amino;    -   R¹² and R¹³, with the nitrogen atom to which they are attached,        may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl,        azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be        unsubstituted, once or twice substituted by a group selected        from fluoro, methyl, methoxy, gemdimethyl, amino, aminocarbonyl,        hydroxy, oxetanylamino, methylpiperazinyl and aminomethyl;    -   R¹² and R¹³, with the nitrogen atom to which they are attached        may form a bridge ring or a spiral ring selected from        2-oxa-6-aza-spiro[3.4]octan-6-yl,        2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl,        (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,        4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-5-yl,        2-aza-bicyclo[2.1.1]hexan-2-yl or        3-aza-bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or        further substituted by amino; and all the remaining substituents        are as defined above in embodiment (i) or (ii).

Another embodiment of present invention is (iv) a compound of formula(I) or a pharmaceutically acceptable salt thereof, wherein

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are hydrogen;

-   -   A is —C—R¹¹, wherein R¹¹ is hydrogen, halogen or C₁₋₆alkyl;    -   X is S;    -   Y is —CH— or nitrogen;    -   Q is NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen; and the        other one is amino(CH₂)₂₋₆, amino(CH₂)₁₋₆difluoromethyl(CH₂)₁₋₆,        amino(CH₂)₀₋₆oxetanyl(CH₂)₁₋₆ or hydrogen;

-   R¹² and R¹³, with the nitrogen atom to which they are attached, may    form a pyrrolidinyl ring, which may be once substituted by amino;    and all the remaining substituents are as defined above in    embodiment (i) to (iii).

Further embodiment of present invention is (v) a compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are hydrogen;

-   -   A is —C—R¹¹, wherein R¹¹ is hydrogen, chloro or methyl;    -   Q is NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen; and the        other one is aminoethyl, aminomethyldifluoromethylmethyl,        aminomethyloxetanylmethyl, aminooxetanylmethyl or hydrogen;    -   R¹² and R¹³, with the nitrogen atom to which they are attached,        may form a pyrrolidinyl ring, which may be once substituted by        amino; and all the remaining substituents are as defined above        in embodiment (iv).

Another further embodiment of present invention is (vi) a compound offormula (I) or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are hydrogen;    -   A is —C—R¹¹, wherein R¹¹ is hydrogen, halogen, C₁₋₆alkyl,        hydroxy(CH₂)₁₋₆, deuteratedmethyl or carboxyl;    -   X is S═O;    -   Y is —CH— or nitrogen;    -   Q is NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen; and the        other one is amino(CH₂)₂₋₆; amino(CH₂)₁₋₆difluoromethyl(CH₂)₁₋₆;        amino(CH₂)₁₋₆fluoromethyl(CH₂)₁₋₆; amino(CH₂)₁₋₆oxetanyl;        amino(CH₂)₁₋₆oxetanyl(CH₂)₁₋₆; aminooxetanyl(CH₂)₁₋₆;        hydroxy(CH₂)₂₋₁₀; phenyl(CH₂)₁₋₆aminooxetanyl(CH₂)₁₋₆;        pyrrolidin-3-yl, 4-substituted by halogen;    -   or

-   -    wherein R¹⁴ is hydrogen, R¹⁵ is hydroxy, and R¹⁶ is        hydroxy(CH₂)₁₋₆;    -   R¹² and R¹³, with the nitrogen atom to which they are attached,        may form a pyrrolidinyl ring, which may be once or twice        substituted by a group selected from halogen, amino and        hydroxyl; and all the remaining substituents are as defined        above in embodiment (i) to (v).

More further embodiment of present invention is (vii) a compound offormula (I) or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are hydrogen;    -   A is —C—R¹¹, wherein R¹¹ is hydrogen, chloro, methyl,        hydroxymethyl, deuteratedmethyl or carboxyl;    -   Q is NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen; and the        other one is aminoethyl; aminomethyldifluoromethylmethyl;        aminomethylfluoromethylmethyl; aminomethyloxetanyl;        aminomethyloxetanylmethyl; aminooxetanylmethyl; aminopropyl;        hydroxyethyl; phenylmethylaminooxetanylmethyl; pyrrolidin-3-yl,        4-substituted by fluoro;    -   or

-   -    wherein R¹⁴ is hydrogen, R¹⁵ is hydroxy, and R¹⁶ is        hydroxymethyl;    -   R¹² and R¹³, with the nitrogen atom to which they are attached,        may form a pyrrolidinyl ring, which may be once or twice        substituted by a group selected from fluoro, amino and hydroxyl;        and all the remaining substituents are as defined above in        embodiment (vi). Still further embodiment of present invention        is (viii) a compound of formula (I) or a pharmaceutically        acceptable salt thereof, wherein    -   R¹, R², and R³ are hydrogen, halogen or C₁₋₆alkyl;    -   R⁴ is hydrogen or C₁₋₆alkyl;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen, halogen, hydroxy, C₁₋₆alkoxy, morpholinyl or        4-(propan-2-yl)piperazin-1-yl;    -   R⁷ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy,        hydroxy(CH₂)₂₋₆—O—, or phenoxy;    -   R⁸ is hydrogen, halogen or C₁₋₆alkoxy;    -   R⁹ is hydrogen or C₁₋₆alkyl;    -   R¹⁰ is hydrogen;    -   A is nitrogen or —C—R¹¹, wherein R¹¹ is hydrogen, halogen,        C₁₋₆alkyl, C₁₋₆alkoxy, trifluoromethyl, trifluoromethoxy,        pyridinyloxy, C₁₋₆alkoxy(CH₂)₁₋₆—O—, difluoromethoxy, nitro,        cycloalkyl, cyano, amino, vinyl, acetylenyl, aminocarbonyl,        hydroxy(CH₂)₂₋₆—O—, C₁₋₆alkylsulfanyl, C₁₋₆alkylsulfinyl,        hydroxy(CH₂)₁₋₆, deuteratedmethyl, carboxyl, C₁₋₆alkoxycarbonyl,        hydroxy, difluoromethyl or methylCH(hydroxy)-;    -   X is SO₂;    -   Y is —CH— or nitrogen;    -   Q is 2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl; amino(CH₂)₂₋₆—O—;        amino(CH₂)₂₋₆aminosulfonyl; C₁₋₆alkyl, unsubstituted or once        substituted by amino; carboxy(CH₂)₁₋₆; phenylsulfonyl;        piperidin-4-yl-carbonyl; piperidin-4-yloxy; 1H-pyrazol-3-yl;        pyrrolidin-3-yloxy; or NR¹²R¹³, wherein one of R¹² and R¹³ is        hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₂₋₆; and the other one is        {1-[amino(CH₂)₀₋₆]-3,3-difluorocyclobutyl}(CH₂)₁₋₆;        (S—C₁₋₆alkylsulfonimidoyl)(CH₂)₂₋₆;        3-aminotetrahydrofuran-3-yl(CH₂)₁₋₆;        (2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl;        3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;        3-(aminomethyl)thietan-3-ylmethyl;        (1,1-dioxidothiomorpholin-4-yl)ethyl;        C₀₋₆alkyl(oxetanyl)N(CH₂)₂₋₆; 4,5-dihydro-1H-imidazol-2-yl;        amino(CH₂)₂₋₆—O—(CH₂)₂₋₆; amino(CH₂)₂₋₁₀; amino(CH₂)₁₋₆        carbonyl; aminocarbonyl(CH₂)₁₋₆;        amino(CH₂)₁₋₆difluoromethyl(CH₂)₁₋₆;        amino(CH₂)₁₋₆difluoromethyldifluoromethyl(CH₂)₁₋₆;        amino(CH₂)₁₋₆fluoromethyl(CH₂)₁₋₆;        amino(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆; amino(CH₂)₀₋₆oxetanyl(CH₂)₁₋₆;        amino(CH₂)₂₋₆sulfanyl(CH₂)₂₋₆; amino(CH₂)₂₋₆sulfonyl(CH₂)₂₋₆;        1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl;        4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl;        1-aminocyclopropylethyl; 1-aminocyclopropylmethyl;        (2-amino-4,5-dihydro-oxazol-5-yl)(CH₂)₁₋₆;        (2-amino-4,5-dihydro-oxazol-4-yl)(CH₂)₁₋₆; aminophenyl;        4-aminotetrahydropyran-4-yl(CH₂)₁₋₆; azetidin-2-yl(CH₂)₁₋₆;        azetidin-3-yl(CH₂)₀₋₆; azetidin-3-ylcarbonyl;        C₁₋₆alkoxy(CH₂)₂₋₆; C₁₋₆alkoxy(CH₂)₂₋₆amino(CH₂)₂₋₆; C₁₋₆alkyl;        C₁₋₆alkylamino(CH₂)₂₋₆; C₁₋₆alkylaminooxetanyl(CH₂)₁₋₆;        C₁₋₆alkylcarbonyl; C₁₋₆alkylcarbonylamino(CH₂)₂₋₆;        C₁₋₆alkylcarbonylamino(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆; C₁₋₆        alkylsulfinyl(CH₂)₂₋₆; C₁₋₆ alkylsulfonyl; carboxy(CH₂)₁₋₆;        cyano(CH₂)₁₋₆; C₁₋₆alkylaminocarbonyl(CH₂)₀₋₆;        diC₁₋₆alkylamino(CH₂)₂₋₆; diC₁₋₆alkylaminocarbonyl;        difluoromethyl(CH₂)₁₋₆ amino(CH₂)₂₋₆; hydrogen;        hydroxy(CH₂)₂₋₁₀; hydroxy(CH₂)₂₋₆amino(CH₂)₂₋₆;        hydroxy(CH₂)₁₋₆carbonyl; hydroxy(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆;        4-hydroxycyclohexyl; isoxazol-3-yl; morpholin-2-yl(CH₂)₁₋₆;        morpholin-4-yl(CH₂)₂₋₆; 2-oxa-6-aza-spiro[3.4]oct-8-yl;        oxetanyl(CH₂)₀₋₆; N-oxetanylpyrrolidin-3-yl;        oxo-pyrrolidin-4-ylcarbonyl; phenylaminocarbonyl;        phenyl(CH₂)₁₋₆aminooxetanyl(CH₂)₁₋₆, phenylcarbonyl;        piperazinyl(CH₂)₂₋₆; piperidin-1-yl(CH₂)₂₋₆;        piperidin-2-yl(CH₂)₁₋₆; piperidin-3-yl(CH₂)₀₋₆;        piperidin-4-yl(CH₂)₀₋₆; piperidin-2-ylcarbonyl;        piperidin-3-ylcarbonyl; piperidin-4-ylcarbonyl;        pyrazin-2-ylcarbonyl; pyrazol-3-yl; pyridazin-3-ylcarbonyl;        pyridine-2-yl(CH₂)₀₋₆carbonyl; pyridine-3-yl(CH₂)₀₋₆carbonyl;        pyridine-2-ylamino(CH₂)₂₋₆; pyrrolidin-3-yl, unsubstituted or        4-substituted by halogen; pyrrolidin-4-yl, unsubstituted or        3-substituted by hydroxy or C₁₋₆alkoxy; pyrrolidin-2-yl(CH₂)₁₋₆;        pyrrolidin-2-ylcarbonyl; tetrahydrofuran-3-yl;        tetrahydropyran-4-yl; tetrazolyl(CH₂)₂₋₆;        trifluoromethylcarbonylamino(CH₂)₁₋₆oxetanyl;        trifluoromethylsulfonyl;

-   -    wherein R¹⁴ is hydrogen or C₁₋₆alkyl; R¹⁵ is hydroxy, C₁₋₆alkyl        or amino; and R¹⁶ is C₁₋₆alkyl, trifluoromethyl,        hydroxy(CH₂)₁₋₆, amino(CH₂)₁₋₆, aminocarbonyl or        carboxy(CH₂)₁₋₆;

-   -    wherein R¹⁷ is hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₁₋₆; R¹⁸ is        hydroxy(CH₂)₁₋₆ or C₁₋₆alkyl; R¹⁹ is hydroxy(CH₂)₁₋₆,        amino(CH₂)₁₋₆, carboxy or aminocarbonyl(CH₂)₀₋₆;    -   or

-   -    wherein R²⁰ is hydrogen or C₁₋₆alkyl; R²¹ is C₁₋₆alkyl; R²² is        C₁₋₆alkoxy or amino;    -   R¹² and R¹³, with the nitrogen atom to which they are attached,        may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl,        azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be        unsubstituted, once or twice substituted by a group selected        from halogen, C₁₋₆alkyl, C₁₋₆alkoxy, gemdimethyl, amino,        aminocarbonyl, hydroxy, oxetanylamino, C₁₋₆alkylpiperazinyl and        amino(CH₂)₁₋₆;    -   R¹² and R¹³, with the nitrogen atom to which they are attached        may form a bridge ring or a spiral ring selected from        2-oxa-6-aza-spiro[3.4]octan-6-yl,        2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl,        (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,        4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-5-yl,        2-aza-bicyclo[2.1.1]hexan-2-yl or        3-aza-bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or        further substituted by amino; and all the remaining substituents        are as defined above in embodiment (i) to (vii).

Particular embodiment of present invention is (ix) a compound of formula(I) or a pharmaceutically acceptable salt thereof, wherein R¹, R², andR³ are hydrogen, fluoro, chloro or methyl;

-   -   R⁴ is hydrogen or methyl;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen, fluoro, hydroxy, methoxy, morpholinyl or        4-(propan-2-yl)piperazin-1-yl;    -   R⁷ is hydrogen, fluoro, chloro, methyl, methoxy, hydroxyethoxy,        or phenoxy;    -   R⁸ is hydrogen, fluoro or methoxy;    -   R⁹ is hydrogen or methyl;    -   R¹⁰ is hydrogen;    -   A is nitrogen or —C—R¹¹, wherein R¹¹ is hydrogen, fluoro,        chloro, bromo, methyl, ethyl, methoxy, trifluoromethyl,        trifluoromethoxy, pyridinyloxy, methoxyethoxy, difluoromethoxy,        nitro, cyclopropyl, cyano, amino, vinyl, acetylenyl,        aminocarbonyl, hydroxyethoxy, methylsulfanyl, methylsulfinyl,        hydroxymethyl, deuteratedmethyl, carboxyl, methoxycarbonyl,        hydroxy, difluoromethyl or methylCH(hydroxy)-;    -   Y is —CH— or nitrogen;    -   Q is 2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl; aminoethoxy;        aminoethylaminosulfonyl; aminopropyl; carboxyethyl; methyl;        phenylsulfonyl; piperidin-4-yl-carbonyl; piperidin-4-yloxy;        1H-pyrazol-3-yl; pyrrolidin-3-yloxy; or NR¹²R¹³, wherein one of        R¹² and R¹³ is hydrogen, methyl or hydroxyethyl, and the other        one is aminobutyl; aminocarbonylethyl; aminocarbonylmethyl;        1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl;        4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl;        1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; aminodecyl;        (2-amino-4,5-dihydro-oxazol-5-yl)methyl;        (2-amino-4,5-dihydro-oxazol-4-yl)methyl; aminoethoxyethyl;        aminoethyl; aminoethylcarbonyl; aminoethylfluoromethylmethyl;        aminoethylsulfanylethyl; aminoethylsulfonylethyl; aminoheptyl;        aminohexyl; aminomethylcarbonyl;        (1-aminomethyl-3,3-difluorocyclobutyl)methyl;        aminomethyldifluoromethyldifluoromethylmethyl;        aminomethyldifluoromethylmethyl;        (2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl;        3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;        aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl;        aminomethyloxetanyl; aminomethyloxetanylmethyl;        3-(aminomethyl)thietan-3-ylmethyl; aminononyl; aminooctyl;        aminooxetanylethyl; aminooxetanylmethyl; aminopentyl;        aminophenyl; aminopropyl; 4-aminotetrahydropyran-4-ylmethyl;        3-aminotetrahydrofuran-3-ylmethyl; azetidin-3-yl;        azetidin-3-ylcarbonyl; azetidin-2-ylmethyl; azetidin-3-ylmethyl;        carboxyethyl; carboxymethyl; cyanoethyl;        difluoromethylmethylaminoethyl; 4,5-dihydro-1H-imidazol-2-yl;        dimethylaminocarbonyl; dimethylaminoethyl;        (1,1-dioxidothiomorpholin-4-yl)ethyl; ethyl; ethylaminocarbonyl;        ethylaminoethyl; ethylaminooxetanylmethyl; ethyl        (oxetanyl)aminoethyl; hydrogen; 4-hydroxycyclohexyl;        hydroxyethyl; hydroxyethylaminoethyl; hydroxyethyloxetanyl;        hydroxymethylcarbonyl; hydroxymethyloxetanylmethyl;        hydroxynonyl; hydroxypropyl; isoxazol-3-yl; methoxyethyl;        methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl;        methylaminoethyl; methylcarbonyl; methylcarbonylaminoethyl;        methylcarbonylaminomethyloxetanylmethyl;        methylcarbonylaminopropyl; methylsulfinylethyl;        2-(S-methylsulfonimidoyl)ethyl; methylsulfonyl;        morpholin-4-ylethyl; morpholin-2-ylmethyl;        2-oxa-6-aza-spiro[3.4]oct-8-yl; oxetanyl; oxetanylaminoethyl;        oxetanylaminopropyl; oxetanylmethyl; N-oxetanylpyrrolidin-3-yl;        oxo-pyrrolidin-4-ylcarbonyl; phenylaminocarbonyl;        phenylcarbonyl; phenylmethylaminooxetanylmethyl;        piperazin-1-ylethyl; piperidin-2-ylcarbonyl;        piperidin-3-ylcarbonyl; piperidin-4-ylcarbonyl; piperidine-3-yl;        piperidine-4-yl; piperidin-1-ylethyl; piperidin-2-ylmethyl;        pyrazin-2-ylcarbonyl; pyrazol-3-yl; pyridazin-3-ylcarbonyl;        pyridine-2-ylmethylcarbonyl; pyridine-2-ylaminoethyl;        pyridine-2-ylcarbonyl; pyridine-3-ylcarbonyl; pyrrolidin-3-yl,        unsubstituted or 4-substituted by fluoro; pyrrolidin-4-yl,        unsubstituted or 3-substituted by hydroxy or methoxy;        pyrrolidin-2-ylmethyl; pyrrolidin-2-ylcarbonyl;        tetrahydrofuran-3-yl; tetrahydropyran-4-yl; tetrazolylethyl;        trifluoromethylsulfonyl;        trifluoromethylcarbonylaminomethyloxetanyl;

-   -    wherein R¹⁴ is hydrogen or methyl; R¹⁵ is hydroxy, methyl or        amino; and R¹⁶ is methyl, trifluoromethyl, hydroxymethyl,        hydroxyethyl, aminomethyl, aminocarbonyl or carboxymethyl;

-   -    wherein R¹⁷ is hydrogen, methyl or hydroxymethyl; R¹⁸ is        hydroxymethyl or methyl; R¹⁹ is hydroxymethyl, aminomethyl,        carboxy, aminocarbonyl or aminocarbonylmethyl; or

-   -    wherein R²⁰ is hydrogen or methyl; R²¹ is methyl or ethyl; R²²        is methoxy or amino;    -   R¹² and R¹³, with the nitrogen atom to which they are attached,        may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl,        azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be        unsubstituted, once or twice substituted by a group selected        from fluoro, methyl, methoxy, gemdimethyl, amino, aminocarbonyl,        hydroxy, oxetanylamino, methylpiperazinyl and aminomethyl;    -   R¹² and R¹³, with the nitrogen atom to which they are attached        may form a bridge ring or a spiral ring selected from        2-oxa-6-aza-spiro[3.4]octan-6-yl,        2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl,        (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,        4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-5-yl,        2-aza-bicyclo[2.1.1]hexan-2-yl or        3-aza-bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or        further substituted by amino; and all the remaining substituents        are as defined above in embodiment (viii).

Another particular embodiment of present invention is (x) a compound offormula (I) or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are hydrogen;    -   A is —C—R¹¹, wherein R¹¹ is C₁₋₆alkyl;    -   X is S(O)NH;    -   Y is —CH—;    -   Q is NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen; and the        other one is amino(CH₂)₂₋₆;    -   R¹² and R¹³, with the nitrogen atom to which they are attached,        may form a pyrrolidinyl ring, which may be twice substituted by        a group selected from amino and hydroxyl; and all the remaining        substituents are as defined above in embodiment (i) to (ix).

Still another particular embodiment of invention is (xi) a compound offormula (I) or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are hydrogen;    -   A is —C—R¹¹, wherein R¹¹ is methyl;    -   Q is NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen; and the        other one is aminoethyl;    -   R¹² and R¹³, with the nitrogen atom to which they are attached,        may form a pyrrolidinyl ring, which may be twice substituted by        a group selected from amino and hydroxyl; and all the remaining        substituents are as defined above in embodiment (x).

Particular embodiment of present invention is a compound of formula (I)or a pharmaceutically acceptable salt thereof, selected from:N-[(3-aminooxetan-3-yl)methyl]-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(8-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(9-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(8-chloro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[(3-aminotetrahydrofuran-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(4-aminotetrahydro-2H-pyran-4-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(2-oxa-6-azaspiro[3.4]oct-8-yl)quinolin-4-amine;N-[2-(3-aminooxetan-3-yl)ethyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(5-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-amine;N-[(1-aminocyclohexyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(8-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-{[3-(benzylamino)oxetan-3-yl]methyl}-6-chloro-2-(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-{[3-({[2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}methyl)oxetan-3-yl]methyl}acetamide;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;[3-({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}methyl)oxetan-3-yl]methanol;(2S)-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol;(2R)-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol;N-{[1-(aminomethyl)-3,3-difluorocyclobutyl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;trans-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclohexane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclohexane-1,3-diamine;(3R)-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4-dimethylpyrrolidin-3-ol;cis-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclohexane-1,4-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2-difluoropropane-1,3-diamine;N-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2,2-difluoropropane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-fluoropropane-1,3-diamine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;[4-{[(3-aminooxetan-3-yl)methyl]amino}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-fluoro-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-amine;N˜1˜-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2-methylpropane-1,2-diamine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(tetrahydro-2H-pyran-4-yl)quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(piperazin-1-yl)ethyl]quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-4-ylmethyl)quinolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]heptane-1,7-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-methylethane-1,2-diamine;N′-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N,N-dimethylethane-1,2-diamine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N,6-dimethylquinolin-4-aminetrifluoroacetate;(3S,4S)-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3,4-diol;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-2-ylmethyl)quinolin-4-amine;4-[4-(1,4-diazepan-1-yl)-6-methylquinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-ethylethane-1,2-diamine;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}ethanol;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-4-yl)quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-3-yl)quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-2-ylmethyl)quinolin-4-amine;2-[(2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}ethyl)amino]ethanol;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2,3,3-tetrafluorobutane-1,4-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(2-methoxyethyl)ethane-1,2-diamine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-methylpyrrolidin-3-ol;N-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(oxetan-3-yl)quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[(3R)-tetrahydrofuran-3-yl]quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(oxetan-3-ylmethyl)quinolin-4-amine;N-[(1-aminocyclobutyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pentane-1,5-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]hexane-1,6-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-1,1,1-trifluoromethanesulfonamidehydrochloride;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyridazine-3-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]benzamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]acetamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-3-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-4-carboxamide;3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-1,1-dimethylurea;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(1,2-oxazol-3-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(˜2˜H_3_)methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[6-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;N-[(3-aminooxetan-3-yl)methyl]-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;1-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine;N-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2,2-difluoropropane-1,3-diamine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-[2-(1,1-dioxidothiomorpholin-4-yl)ethyl]-6-methylquinolin-4-amine;N-[2-(2-aminoethoxy)ethyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropane-1,2-diamine;N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2-methylpropane-1,2-diamine;N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,2-diamine;4-[6-methyl-4-(4-methylpiperazin-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;1-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-2-ol;(2S)—N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,2-diamine;(2R)—N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,2-diamine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7,8-difluoro-6-methylquinolin-4-amine;N-(2,2-difluoroethyl)-N′-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}oxetan-3-ethanol;N-{[3-(aminomethyl)thietan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-{[3-(aminomethyl)-1,1-dioxidothietan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-(4,5-dihydro-1H-imidazol-2-yl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;trans-4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}cyclohexanol;(2S)-2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol;trans-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-methoxypyrrolidin-3-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin+D154-4(5H)-yl)-N-[trans-4-methoxypyrrolidin-3-yl]-6-methylquinolin-4-amine;4-{4-[(4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]-6-methylquinolin-2-yl}-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;(3R,4R)-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-(4-methylpiperazin-1-yl)pyrrolidin-3-ol;N-{2-[(2-aminoethyl)sulfanyl]ethyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;1-{1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidin-4-yl}methanamine;2-{[2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}ethanol;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,3-diamine;4-[6-methyl-4-(morpholin-4-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(piperidin-1-yl)ethyl]quinolin-4-amine;1-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-2-ol;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-fluoroquinolin-4-yl]ethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]ethane-1,2-diamine;N-[7-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;N-[8-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;N-[5-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2-dimethylpropane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine;N˜2˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropane-1,2-diamine;N˜2˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]butane-1,4-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-nitroquinolin-4-yl]ethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-yl]ethane-1,2-diamine;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-yl]amino}ethanol;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-fluoro-6-methylquinolin-4-yl]amino}ethanol;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-fluoro-6-methylquinolin-4-yl]ethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7,8-difluoro-6-methylquinolin-4-yl]ethane-1,2-diamine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-(2-methoxyethyl)-6-methylquinolin-4-amine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidin-4-amine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]pyrrolidin-3-amine;N-[6-(difluoromethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-ethylquinolin-4-amine;2-{[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}ethanol;N-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-N′-methylethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(methylsulfanyl)quinolin-4-yl]propane-1,3-diamine;N-[6-bromo-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;{4-[(2-aminoethyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}methanol;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,3-diol;2,2′-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]imino}diethanol;4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-3-hydroxybutanoicacid;1-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropan-2-ol;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(morpholin-4-yl)ethyl]quinolin-4-amine;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]amino}ethanol;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]nonane-1,9-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]decane-1,10-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]octane-1,8-diamine;9-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}nonan-1-ol;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]octane-1,8-diamine;cis-4-amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-L-alanine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alanine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]benzene-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]benzene-1,4-diamine;(3S)-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol;(3R)-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol;trans-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclopentane-1,2-diamine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidin-3-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N,N,6-trimethylquinolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(trifluoromethoxy)quinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(trifluoromethyl)quinolin-4-yl]propane-1,3-diamine;N-[6-(difluoromethoxy)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methoxyquinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-methylquinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-methylquinolin-4-yl]propane-1,3-diamine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-fluoroquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;(+)-N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine;(−)-N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;2,2-difluoro-N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;N-[6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2,2-difluoropropane-1,3-diamine;N-[6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;2-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}ethanol;trans-4-amino-1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin-3-ol;(1R,5S,6S)-3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-azabicyclo[3.1.0]hexan-6-amine;trans-4-amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol;1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin-3-amine;trans-1-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-4-fluoropyrrolidin-3-amine;trans-4-amino-1-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin-3-ol;trans-1-[6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-4-fluoropyrrolidin-3-amine;2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-azabicyclo[2.1.1]hexan-5-amine;2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[2-(1-aminocyclopropyl)ethyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(morpholin-2-ylmethyl)quinolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-methylethane-1,2-diamine;N-(azetidin-2-ylmethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine;N-[(1-aminocyclopropyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-(azetidin-3-yl)-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;6-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-6-azaspiro[3.4]octan-8-amine;trans-4-amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]pyrrolidin-3-ol;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine;N-(azetidin-3-yl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]azetidin-3-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]prolinamide;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-(trans-4-fluoropyrrolidin-3-yl)-6-methylquinolin-4-amine;trans-4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}pyrrolidin-3-ol;trans-4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}pyrrolidin-3-ol;cis-4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}pyrrolidin-3-ol;N-[trans-4-fluoropyrrolidin-3-yl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;4-[(3-aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-ol;2-({4-[(3-aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}oxy)ethanol;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(2-methoxyethoxy)quinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(pyridin-2-yloxy)quinolin-4-yl]propane-1,3-diamine;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol;3-{[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}propane-1,2-diol;3-{[2-(8-chloro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol;3-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}propane-1,2-diol;3-{[6-methyl-2-(5-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}propane-1,2-diol;N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-[7-(morpholin-4-yl)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-{1,1-dioxido-7-[4-(propan-2-yl)piperazin-1-yl]-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl}-6-methylquinolin-4-amine;3-{[4-(4-aminoquinolin-2-yl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl]oxy}propan-1-ol;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-8-phenoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N˜3˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninamide;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}butanamide;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropanamide;N˜2˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-L-alaninamide;N˜2˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycinamide;N˜2˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-methylglycinamide;(2S)-2-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol;(2R)-2-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol;N-[(2-amino-4,5-dihydro-1,3-oxazol-5-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-{[(4R)-2-amino-4,5-dihydro-1,3-oxazol-4-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-{[(4S)-2-amino-4,5-dihydro-1,3-oxazol-4-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;cis-5-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-2-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycinamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylalaninamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]alaninamide;2-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]butanamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methoxy-2-methylpropanamide;N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4,4-trifluorobutane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninamide;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-{[3-(ethylamino)oxetan-3-yl]methyl}-6-methylquinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[1-(oxetan-3-yl)pyrrolidin-3-yl]quinolin-4-amine;N′-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-ethyl-N-(oxetan-3-yl)ethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(oxetan-3-yl)propane-1,3-diamine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-(oxetan-3-yl)pyrrolidin-3-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(oxetan-3-yl)ethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(pyridin-2-yl)ethane-1,2-diamine;(4R)-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-hydroxypyrrolidin-2-one;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-5-oxopyrrolidine-3-carboxamide;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(1H-pyrazol-3-yl)quinolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyridine-3-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-2-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-(pyridin-2-yl)acetamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]methanesulfonamidetrifluoroacetate;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrazine-2-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-hydroxyacetamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyridine-2-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]azetidine-2-carboxamide;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-phenylurea;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-ethylurea;N-[6-cyclopropyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;4-[(3-aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carbonitrile;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethenylquinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethynylquinolin-4-yl]propane-1,3-diamine;N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-{[3-(benzylamino)oxetan-3-yl]methyl}-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;2-fluoro-N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane-1,3-diamine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;2,2-difluoro-N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane-1,3-diamine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2,2-difluoropropane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-fluoropropane-1,3-diamine;N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane-1,3-diamine;N-[(3-aminooxetan-3-yl)methyl]-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]amino}ethanol;2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-methylpropane-1,2-diamine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;N-[(1-aminocyclobutyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;(−)-N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinazolin-4-amine;(+)-N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinazolin-4-amine;N˜4˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-fluorobutane-1,4-diamine;N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-fluorobutane-1,4-diamine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;trans-4-fluoro-1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-amine;N-(Azetidin-3-yl)-6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-(2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}ethyl)acetamide;N-{[3-({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}methyl)oxetan-3-yl]methyl}acetamide;N-(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propyl)acetamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]acetamide;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-methylpyrrolidin-3-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(9-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;4-(4-{[(3-aminooxetan-3-yl)methyl]amino}-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepin-7-ol1,1-dioxide;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropane-1,2-diol;4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}butane-1,3-diol;N-[6-methyl-2-(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}oxetan-3-yl)methyl]-2,2,2-trifluoroacetamide;N-[3-(aminomethyl)oxetan-3-yl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;2-(aminomethyl)-2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,3-diol;4-amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-2-one;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(methylsulfinyl)ethyl]quinolin-4-amine;N-{2-[(2-aminoethyl)sulfonyl]ethyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[2-(1-imino-1-oxido-1,2,3,5-tetrahydro-4H-1lambda˜4˜,4-benzothiazepin-4-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(S-methylsulfonimidoyl)ethyl]quinolin-4-amine;trans-4-amino-1-[2-(1-imino-1-oxido-1,2,3,5-tetrahydro-4H-1lambda˜4˜,4-benzothiazepin-4-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol;trans-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-fluoropyrrolidin-3-amine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(methylsulfinyl)quinolin-4-yl]propane-1,3-diamine;4-[(3-aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxamide;1-{4-[(3-aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}ethanol;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propanenitrile;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(1H-tetrazol-5-yl)ethyl]quinolin-4-amine;N˜4˜-(2-aminoethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-4,6-diamine;5-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-5,7-diazaspiro[3.4]octan-6-one;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]amino}propane-1,2-diol;3-{[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}propane-1,2-diol;N-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]ethane-1,2-diamine;N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]ethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]ethane-1,2-diamine;N-[3-(aminomethyl)oxetan-3-yl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-(trans-4-fluoropyrrolidin-3-yl)-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-(trans-4-fluoropyrrolidin-3-yl)-6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-amine;N-(azetidin-3-yl)-6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;(4R)-4-{2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethyl}-4,5-dihydro-1,3-oxazol-2-amine;3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoicacid;3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propan-1-amine;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]oxy}ethanamine;4-[6-methyl-4-(pyrrolidin-3-yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;4-[6-methyl-4-(piperidin-4-yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;4-(4,6-dimethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](piperidin-4-yl)methanone;4-[6-methyl-4-(1H-pyrazol-3-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;4-[6-methyl-4-(phenylsulfonyl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;N-(2-aminoethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinoline-4-sulfonamide;methyl4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate;4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylicacid;[4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-(˜2˜H_3_)methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylicacid;4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylicacid;[4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol;[4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol;N-[(1-aminocyclopropyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;and2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinazolin-4-amine.

Another embodiment of invention is (xii) a compound of formula (I) or apharmaceutically acceptable salt thereof, wherein

-   -   R¹ is hydrogen or halogen;    -   R² and R⁴ are hydrogen;    -   R³ is hydrogen or halogen;    -   R⁵ is hydrogen or halogen;    -   R⁶ is hydrogen, halogen, hydroxy, C₁₋₆alkoxy or carboxy;    -   R⁷ is hydrogen, halogen, C₁₋₆alkoxy, C₁₋₆alkylaminocarbonyl,        diC₁₋₆ alkylaminocarbonyl or C₁₋₆alkylsulfonyl;    -   R⁸ is hydrogen or halogen;    -   R⁹ is hydrogen or ═O;    -   R¹⁰ is hydrogen or ═O, provided that R⁹ and R¹⁰ are not ═O        simultaneously;    -   A is —C—R¹¹, wherein R¹¹ is hydrogen, halogen, C₁₋₆alkyl,        C₁₋₆alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy,        difluoromethoxy or C₁₋₆alkylsulfonyl;    -   X is —CH₂—, —O—, NH—, —CF₂, —C(CH₃)(OH)—, C═O, or        —C(═N—C₁₋₆alkoxy)-;    -   Y is —CH— or nitrogen;    -   Q is hydrogen; halogen; C₁₋₆alkyl, once or twice substituted by        hydroxy provided that disubstitution of hydroxy is not on the        same carbon; amino(CH₂)₂₋₆aminosulfonyl;        2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl; or NR¹²R¹³, wherein        one of R¹² and R¹³ is hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₂₋₆,        and the other one is guanidino(CH₂)₂₋₆;        3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;        3-amino-1,1-dioxidothietan-3-ylmethyl;        3-(aminomethyl)thietan-3-ylmethyl; amino(CH₂)₂₋₆—O—(CH₂)₂₋₆;        amino(CH₂)₂₋₁₀; amino(CH₂)₁₋₆carbonyl;        amino(CH₂)₁₋₆difluoromethyl(CH₂)₁₋₆;        amino(CH₂)₁₋₆oxetanyl(CH₂)₁₋₆; amino(CH₂)₂₋₆sulfonyl(CH₂)₂₋₆;        3-aminocyclohexyl; 4-amino cyclohexyl;        2-amino-4,5-dihydro-oxazol-5-yl(CH₂)₁₋₆; aminooxetanyl(CH₂)₁₋₆;        C₁₋₆alkylamino(CH₂)₂₋₆; C₁₋₆alkylamino carbonyl;        diC₁₋₆alkylamino(CH₂)₂₋₆; hydroxy(CH₂)₂₋₆; piperazinyl(CH₂)₂₋₆;        pyrrolidin-3-yl; or

-   -    wherein R¹⁴ is hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₁₋₆; R¹⁵ is        hydroxy, hydroxy(CH₂)₁₋₆ or amino; and R¹⁶ is C₁₋₆alkyl,        hydroxy(CH₂)₁₋₆ or amino(CH₂)₁₋₆;    -   R¹² and R¹³, with the nitrogen atom to which they are attached,        may form a pyrrolidinyl, piperazinyl or diazepanyl ring; which        may be unsubstituted, once or twice substituted by a group        selected from C₁₋₆alkyl, amino or hydroxy.

Another particular embodiment of invention is (xiii) a compound offormula (I) or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is hydrogen or chloro;    -   R² and R⁴ are hydrogen;    -   R³ is hydrogen or chloro;    -   R⁵ is hydrogen or fluoro;    -   R⁶ is hydrogen, fluoro, hydroxy, methoxy, ethoxy or carboxy;    -   R⁷ is hydrogen, fluoro, bromo, methoxy, dimethylaminocarbonyl,        methylsulfonyl or ethylsulfonyl;    -   R⁸ is hydrogen or chloro.    -   A is CR¹¹, wherein R¹¹ is hydrogen, fluoro, chloro, bromo,        methyl, methoxy, trifluoromethyl, trifluoromethoxy,        pyridinyloxy, difluoromethoxy or methylsulfonyl;    -   Q is hydrogen; chloro; hydroxymethyl;        hydroxymethyl(hydroxy)ethyl; aminoethylaminosulfonyl;        2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl; or NR¹²R¹³, wherein        one of R¹² and R¹³ is hydrogen, methyl or hydroxyethyl, and the        other one is aminobutyl; 3-aminocyclohexyl; 4-aminocyclohexyl;        2-amino-4,5-dihydro-oxazol-5-ylmethyl;        3-amino-1,1-dioxidothietan-3-ylmethyl; aminoethoxyethyl;        aminoethyl; aminoethylsulfonylethyl; aminomethylcarbonyl;        aminomethyldifluoromethylmethyl;        3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;        3-(aminomethyl)thietan-3-ylmethyl; aminomethyloxetanylmethyl;        aminooxetanylmethyl; aminopropyl; dimethylaminoethyl;        ethylaminocarbonyl; guanidinoethyl; hydroxyethyl; hydroxypropyl;        methylaminoethyl; piperazin-1-ylethyl; pyrrolidin-3-yl; or

-   -    wherein R¹⁴ is hydrogen, methyl or hydroxymethyl; R¹⁵ is        hydroxy, hydroxymethyl or amino; and R¹⁶ is methyl,        hydroxymethyl or aminomethyl;    -   R¹² and R¹³, with the nitrogen atom to which they are attached,        may form a pyrrolidinyl, piperazinyl or diazepanyl ring; which        may be unsubstituted, once or twice substituted by a group        selected from methyl, amino or hydroxy; and all the remaining        substituents are as defined above in embodiment (xii).

A particular embodiment of present invention is a compound of formula(I) or a pharmaceutically acceptable salt thereof, selected from:N-[(3-aminooxetan-3-yl)methyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine;N-[2-(2-aminoethoxy)ethyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-N′-methylethane-1,2-diamine;1-amino-3-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}propan-2-ol;3-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol;3-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}propan-1-ol;2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methyl-N-[2-(piperazin-1-yl)ethyl]quinolin-4-amine;N˜1˜-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]propane-1,2-diamine;cis-N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]cyclohexane-1,4-diamine;2-(9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine;2,2′-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]imino}diethanol;N˜1˜-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-2-methylpropane-1,2-diamine;5,5-difluoro-2-[6-methyl-4-(4-methylpiperazin-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine;1-[2-(9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)-6-methylquinolin-4-yl]-3-ethylurea;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine;5,5-difluoro-2-[6-methyl-4-(piperazin-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine;2-[4-(1,4-diazepan-1-yl)-6-methylquinolin-2-yl]-5,5-difluoro-2,3,4,5-tetrahydro-1H-2-benzazepine;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-N-methylethane-1,2-diamine;1-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine;2-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}ethanol;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]cyclohexane-1,3-diamine;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-N,N-dimethylethane-1,2-diamine;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]propane-1,3-diamine;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]butane-1,4-diamine;trans-4-amino-1-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol;N-{[3-(aminomethyl)-1,1-dioxidothietan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine;N-{2-[(2-aminoethyl)sulfonyl]ethyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine;N-{[3-(aminomethyl)thietan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine;2-(aminomethyl)-2-({[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-yl]amino}methyl)propane-1,3-diol;2-(4-{[(3-aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-ol;N-[(3-aminooxetan-3-yl)methyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine;N-[(3-amino-1,1-dioxidothietan-3-yl)methyl]-2(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-yl]-2,2-difluoropropane-1,3-diamine;N-[2-(7-bromo-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-chloroquinolin-4-yl]ethane-1,2-diamine;2-{4-[(2-aminoethyl)amino]quinolin-2-yl}-2,3,4,5-tetrahydro-1H-2-benzazepin-8-ol;N-[6-methyl-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(8-fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine;N-[6-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[6-chloro-2-(9-fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(8-fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;1-amino-3-{[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-oltrifluoroacetate;N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[6-bromo-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[6-methoxy-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(6-chloro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(7-fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine;N-methyl-N′-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(7-methoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(7-fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(8-methoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[6-(difluoromethoxy)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-(trifluoromethyl)quinolin-4-yl]ethane-1,2-diamine;N-[8-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[6-fluoro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N,N-dimethyl-N′-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-(trifluoromethoxy)quinolin-4-yl]ethane-1,2-diamine;N-[6-(methylsulfonyl)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;2-{4-[(2-aminoethyl)amino]quinolin-2-yl}-2,3,4,5-tetrahydro-1H-2-benzazepine-8-carboxylicacid; 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine;N-[5-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-{2-[7-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]quinolin-4-yl}ethane-1,2-diamine;N-{2-[7-(ethylsulfonyl)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]quinolin-4-yl}ethane-1,2-diamine;N-[2-(8-ethoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[6-(pyridin-2-yloxy)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;2-{4-[(2-amino ethyl)amino]-6-chloroquinolin-2-yl}-N,N-dimethyl-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxamide;2-{4-[(2-aminoethyl)amino]quinolin-2-yl}-7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;1-(2-{[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}ethyl)guanidinetrifluoroacetate;N-[(2-amino-4,5-dihydro-1,3-oxazol-5-yl)methyl]-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-aminetrifluoroacetate;N-[(2-amino-4,5-dihydro-1,3-oxazol-5-yl)methyl]-6-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine;N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]glycinamide;3-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propan-1-amine;[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]methanol;2-(6-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine;3-[6-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propane-1,2-diol;(4S)-4-{2-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethyl}-4,5-dihydro-1,3-oxazol-2-amine;N-(2-aminoethyl)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-sulfonamidetrifluoroacetate;4-{4-[(2-aminoethyl)amino]-6-methylquinolin-2-yl}-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one;N-[6-methyl-2-(1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(2,3-dihydro-1,4-benzoxazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;N-[(3-aminooxetan-3-yl)methyl]-2-[(5E)-5-(methoxyimino)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]-6-methylquinolin-4-amineand2-(4-{[(3-aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-1,2,3,4-tetrahydro-5H-2-benzazepin-5-one.

The compounds of the present invention can be prepared by anyconventional means. Suitable processes for synthesizing these compoundsas well as their starting materials are provided in the schemes belowand in the examples. All substituents, in particular, R¹ to R¹⁰, A, Q, Xand Y are as defined above unless otherwise indicated. Furthermore, andunless explicitly otherwise stated, all reactions, reaction conditions,abbreviations and symbols have the meanings well known to a person ofordinary skill in organic chemistry.

ABBREVIATIONS

-   -   DMSO-d6: deuterated dimethylsulfoxide    -   FBS: fetal bovine serum    -   g: gram    -   μg: microgram    -   EC₅₀: the concentration of a compound where 50% of its maximal        protection effect against viral induced CPE is observed    -   HPLC: high performance liquid chromatography    -   Hz: Hertz    -   CDCl₃ deuterated chloroform    -   CD₃OD: deuterated methanol    -   mg: milligram    -   MHz: megahertz    -   mL: milliliter    -   mmol: millimole    -   obsd. Observed    -   μL: microliter    -   μm: micrometer    -   μM: micromoles per liter    -   mm: millimeter    -   MS (ESI): mass spectroscopy (electron spray ionization)    -   NMR: nuclear magnetic resonance    -   TLC: thin layer chromatography

General Synthetic Route for 2,4-Dihalogen Quinolines IIIa (Scheme 1)

Compounds of interest of formula IIIa can be prepared according toScheme 1. Starting with various VII, cyclization reaction withpropanedioic acid in the presence of VI affords 2,4-dihalogen-quinolinesIIIa. The reaction can be carried out at a temperature between 100° C.and 150° C. for 6 to 12 hours. VI can be phosphoryl trichloride orphosphoryl tribromide. General synthetic route for2,3,4,5-tetrahydro-1,4-benzothiazepines (Scheme 2)

Compounds of interest IVa, IVb, IVc and IVd can be prepared according toScheme 2. Starting with 2-sulfanylbenzoic acids X, esterification withmethanol gives methyl 2-sulfanylbenzoates IXa. Annulation of esters IXawith 2-bromo ethylamine affords3,4-dihydro-1,4-benzothiazepin-5(2H)-ones VIIIa. Reduction of VIIIaaffords 2,3,4,5-tetrahydro-1,4-benzothiazepines IVa. Acylation of IVagenerates amides IVb. Oxidation of IVb followed by deacylation affordscompounds of interest IVc and IVd.

Methyl 2-sulfanylbenzoates IXa can be prepared by esterification of2-sulfanylbenzoic acids X. The conversion can be achieved by heatingunder reflux in the presence of sulfuric acid in methanol overnight orstirring with thionyl chloride in methanol at room temperature forseveral hours.

3,4-Dihydro-1,4-benzothiazepin-5(2H)-ones VIIIa can be prepared frommethyl 2-sulfanylbenzoates IXa by annulation with 2-bromo-ethylaminehydrochloride. The reaction can be carried out with a standard basicagent such as sodium hydride, potassium tert-butoxide in a suitableorganic solvent such as tetrahydrofuran, 1,4-dioxane,N,N-dimethylformamide or mixtures thereof, typically at 0° C., followedby stirring at room temperature overnight.

2,3,4,5-Tetrahydro-1,4-benzothiazepines IVa can be prepared by reductionof 3,4-dihydro-1,4-benzothiazepin-5(2H)-ones VIIIa. The reaction can becarried out with a standard reducing agent such as lithium aluminiumhydride, boron hydride or combination of sodium borohydride and borontrifluoride in a suitable inert organic solvent such as tetrahydrofuran,diethyl ether or mixtures thereof, typically at 0° C., followed bystirring at a temperature between 25° C. and 70° C. for several hours.

Amides IVb can be prepared by acylation of IVa with acetyl chloride oracetic anhydride. The reaction can be carried out with a suitable basesuch as triethylamine or pyridine in a suitable inert organic solventsuch as dichloromethane, tetrahydrofuran or pyridine at 0° C., followedby stirring at room temperature for 30 minutes.

Compounds IVc can be prepared by oxidation of IVb followed bydeacylation. Oxidation can be carried out with 1-2 equivalents of3-chloroperoxybenzoic acid, in a suitable solvent such asdichloromethane, chloroform, 1,2-dichloroethane, or the mixture thereof,typically at 0° C., followed by stirring at room temperature for 10 to20 minutes. Deacylation can be achieved by stirring amides with asuitable base such as sodium hydroxide or potassium hydroxide in amixture of alcohol such as methanol or ethanol and water under refluxovernight.

Compounds IVd can be prepared by oxidation of IVb followed bydeacylation. Oxidation can be carried out with 4 equivalents of3-chloroperoxybenzoic acid, in a suitable solvent such asdichloromethane, chloroform, 1,2-dichloroethane, or the mixture thereof,typically at 0° C., followed by stirring at room temperature for 1 to 2hours. Deacylation can be achieved by stirring amides with a suitablebase such as sodium hydroxide or potassium hydroxide in a mixture ofalcohol such as methanol or ethanol and water under reflux overnight.

General Synthetic Route for5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepines (Scheme 3)

Compounds of interest IVe can be prepared according to Scheme 3.Starting from 1-(2-sulfanylphenyl)ethanones IXb, annulation of estersIXb with 2-bromo ethylamine hydrochloride affords5-methyl-2,3-dihydro-1,4-benzothiazepines VIIIb. Reduction of VIIIbaffords 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepines IVe.

5-Methyl-2,3-dihydro-1,4-benzothiazepine VIIIb can be prepared from1-(2-sulfanylphenyl)ethanones IXb by annulation with 2-bromo-ethylamine.The reaction can be carried out with a standard basic agent such assodium hydride, potassium tert-butoxide in a suitable organic solventsuch as tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or mixturesthereof, typically at 0° C., followed by stirring at room temperatureovernight.

5-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepines IVe can be preparedfrom reduction of 5-methyl-2,3-dihydro-1,4-benzothiazepines VIIIb. Thereaction can be carried out with a reducing reagent such as sodiumborohydride in a suitable organic solvent such as methanol, water ormixtures thereof at room temperature for several hours or overnight,followed by treatment with concentrated hydrochloric acid at roomtemperature for 30 minutes. After neutralization with sodium carbonateor sodium hydroxide, free form of IVe is obtained.

General Synthetic Route for Formulas Iaa (Scheme 4)

Compounds of interest Iaa can be prepared according to Scheme 4.Coupling of 2,4-dihalogen quinolines IIIa with benzothiazepines IVffollowed by oxidation gives 4-halogen quinolines IIab. Coupling of4-halogen quinolines IIab with various benzyl diamines Va followed bydebenzylation generates Iaa.

Quinolines IIac can be prepared by coupling of 2,4-dihalogen quinolinesIIIa with benzothiazepines IVf. The reaction can be carried out with orwithout a solvent such as isopropanol, n-butanol, tert-butanol or themixture thereof at a temperature between 120° C. and 180° C., typicallyat 160° C. under microwave irradiation for several hours.

Sulfones IIab can be prepared by oxidation of sulfides IIac. Thereaction can be carried out with a suitable oxidant such as3-chloroperoxybenzoic acid in a suitable inert organic solvent such asdichloromethane typically at 0° C., followed by stirring at roomtemperature for several hours. Alternatively, the reaction can becarried out with a suitable oxidant such as hydrogen peroxide, sodiumperiodate or potassium permanganate, in a suitable solvent such asmethanol, tetrahydrofuran, water or the mixture thereof, typically at 0°C., followed by stirring at a temperature between room temperature and70° C. for several hours.

4-Benzyl diamino quinolines IIaa can be prepared by coupling ofquinolines IIab with various benzyl diamines Va. The reaction can becarried out in the presence of a palladium catalyst such as1,1′-bis(diphenylphosphino)ferrocene-palladium (II), palladium (II)acetate, tri(dibenzylideneacetone)dipalladium(0), or palladium (II)chloride in the presence of a phosphine ligand such as triphenylphosphane, 1,1′-bis(diphenylphosphino)ferrocene,9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, ortricyclohexylphosphine, with a suitable base such as sodium carbonate,potassium carbonate, cesium carbonate, sodium tert-butoxide or potassiumtert-butoxide, in a suitable inert organic solvent such as toluene,1,4-dioxane, tetrahydrofuran or N,N-dimethylformamide at a temperaturebetween 100° C. and 160° C. for 1 to 3 hours under microwaveirradiation. Alternatively, the reactions can be carried out at a heatedtemperature such as between 100° C. and 140° C. for a longer reactiontime without microwave irradiation.

Compounds of interest Iaa can be prepared by standard debenzylation ofIIaa. The reaction can be carried out in the presence of palladium oncarbon, palladium hydroxide on carbon or platinum oxide, typically withan acid such as hydrochloric acid, acetic acid or trifluoroacetic acidin a suitable solvent such as methanol, ethanol, tetrahydrofuran, ethylacetate or the mixture thereof, at room temperature for several hoursunder hydrogen atmosphere.

General Synthetic Route for Formula Iab and Iac (Scheme 5)

Compounds of interest Iab and Iac can be prepared according to Scheme 5.Coupling of 4-halogen quinolines IIac with various amines XI affordsIab. Coupling of 4-halogen quinolines IIab and various amines XI affords4-amino quinolines Iac. Alternatively, Iac can be obtained by oxidationof the sulfides Iab.

4-Amino quinolines Iab can be prepared by coupling of 4-halogenquinolines IIac with various amines XI in the presence or absence of apalladium catalyst. Palladium-catalyzed coupling reaction can be carriedout in the presence of a palladium catalyst such as1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride, palladiumacetate or tris(dibenzylideneacetone) dipalladium(0), in combinationwith a phosphine ligand such as 1,1′-bis(diphenylphosphino)ferrocene,2,2′-bis(diphenylphosphino)-1,1′-binaphthalene,4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, and a base suchas sodium tert-butoxide, cesium carbonate or potassium phosphate in asuitable solvent such as 1,4-dioxane or toluene, at a temperaturebetween 100° C. and 140° C. for 1 to 2 hours under microwaveirradiation. Alternatively, palladium-catalyzed coupling reaction can becarried out at an elevated temperature such as 110° C. or 120° C.without microwave irradiation for a longer reaction time. Coupling of4-halogen quinolines IIac with various amines XI in the absence of apalladium catalyst can be carried out with a suitable base such asN,N-diisopropylethylamine or without any base in a suitable solvent suchas n-butanol, 1-methyl-2-pyrrolidinone or phenol, at a temperaturebetween 130° C. and 160° C. for 1.5 to 2 hours under microwaveirradiation. Alternatively, the reaction can be carried out at anelevated temperature between 150° C. and 180° C. without microwaveirradiation for a longer reaction time. Alternatively, the reaction canalso be carried out without any base and without any solvent at 160° C.for one to several hours under microwave irradiation.

4-Amino quinolines Iac can be prepared by coupling of 4-halogenquinolines IIab with various amines XI in the presence of a metalcatalyst such as a palladium catalyst or copper (I) iodide, or absenceof a metal catalyst. Coupling of 4-halogen quinolines IIab with variousamines XI in the presence of a palladium catalyst or in the absence ofany metal catalyst can be carried out in analogy to coupling of4-halogen quinolines IIac with various amines XI. Copper(I) iodidecatalyzed coupling of 4-halogen quinolines IIab with various amines XIcan be carried out in the presence of copper(I) iodide with a ligandsuch as N,N′-dimethylcyclohexane-1,2-diamine or cyclohexane-1,3-diamine,and a base such as potassium carbonate or potassium phosphate in asuitable solvent such as 1,4-dioxane or diethylene glycol dimethylether, at a temperature between 140° C. and 150° C. for 2 to 3 hoursunder microwave irradiation. Alternatively, the reaction can be carriedout at an elevated temperature without microwave irradiation for alonger reaction time.

Alternatively, 4-Amino quinolines Iac can be prepared from oxidation ofsulfides Iab. The reaction can be carried out in analogy to oxidation ofquinolines IIac in Scheme 4.

General Synthetic Route for Formula Iad (Scheme 6)

Compounds of interest Iad can be prepared according to Scheme 6.Coupling of 2,4-halogen quinolines a with benzothiazepines IVg affords2-benzothiazepin-4-halogen quinolines IIad. Coupling of had with variousamines XI affords compounds of interest Iad.

2-Benzothiazepin-4-halogen quinolines IIad can be prepared from couplingof 2,4-halogen quinolines IIIa with benzothiazepines IVg. The reactioncan be carried out in the absence of solvent or in a suitable solventsuch as isopropanol, n-butanol, tert-butanol or the mixtures thereof ata temperature between 120° C. and 180° C., typically at 160° C. undermicrowave irradiation for several hours.

Compounds of interest of formula had can be prepared from coupling of2-benzothiazepin-4-halogen quinolines IIad with various amines XI. Thereaction can be carried out in the presence of a metal catalyst or inthe absence of a metal catalyst in analogy to coupling of 4-halogenquinolines IIab with various amines XI in Scheme 5.

General Synthetic Route for Formula Iae, Iaf and Iag (Scheme 7)

Compounds of interest Iae, Iaf and Iag can be prepared according toScheme 7. Coupling of 4-halogen quinolines IIae with various protectedamines affords intermediates IIaf, IIag and IIah. Deprotection of IIaf,IIag and IIah affords compounds of interest Iae, Iaf and Iag.

Compounds of interest IIaf, IIag and IIah can be prepared from couplingof 4-halogen quinolines IIae with various protected amines. Coupling of4-halogen quinolines IIae with various amines such as tert-butylcarbamate, XII or XIII can be carried out in the presence of a metalcatalyst or in the absence of a metal catalyst in analogy to coupling of4-halogen quinolines IIab with various amines XI in Scheme 5.

Compounds of interest Iae, Iaf and Iag can be prepared from deprotectionof tert-butyloxycarbonyl of IIaf, IIag and IIah. The reaction can becarried out with a suitable acid such as trifluoroacetic acid orhydrochloric acid in a suitable solvent such as dichloromethane, ethylacetate or 1,4-dioxane, at 0° C. to room temperature for 4 to 16 hours.

General Synthetic Route for Formula Iah (Scheme 8)

Compounds of interest Iah can be prepared according to Scheme 8.Coupling of 4-halogen quinolines IIae with various protected amines XIVaffords intermediates IIai. Deprotection of benzyloxycarbonyl of IIaiaffords compounds of interest Iah.

Compounds IIai can be prepared from coupling of 4-halogen quinolinesIIae with various amines XIV. The reaction can be carried out in thepresence of a metal catalyst or in the absence of a metal catalyst inanalogy to coupling of 4-halogen quinolines IIab with various amines XIin Scheme 5. Typically, the reaction can be carried out in the presenceof tris(dibenzylideneacetone)dipalladium(0) with2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, and sodiumtert-butoxide in a suitable solvent such as 1,4-dioxane, at 120° C. for2 hours under microwave irradiation.

Compounds of interest Iah can be prepared from deprotection ofbenzyloxycarbonyl of IIai. The conversion can be achieved under strongacidic conditions, under basic conditions or by hydrogenation. TreatingIIai with a mixture of aqueous solution of potassium hydroxide andmethanol under reflux for 30 minutes to several hours can generate Iah.Treating IIai under strong acidic conditions such as reflux in 6 Nhydrochloride in methanol for several hours can also generate Iah.Hydrogenation of IIai can be carried out in the presence of palladium oncarbon or palladium black, under hydrogen atmosphere or with a hydrogendonor such as formic acid or ammonium formate, in a suitable solventsuch as methanol or ethanol, at a temperature between room temperatureand 80° C. for 15 minutes to several hours.

General Synthetic Route for Formula Iai and Iaj (Scheme 9)

Compounds of interest Iai and Iaj can be prepared according to Scheme 8.Demethylation of 6-methoxy quinolines IIaj affords 6-hydroxy quinolinesIIak. Reaction of IIak with bromides XV affords IIam. Coupling of6-hydroxy quinolines IIak with propane-1,3-diamine affords compounds ofinterest Iai. Coupling of IIam with propane-1,3-diamine affordscompounds of interest Iaj.

6-Hydroxy quinolines IIak can be prepared by demethylation of 6-methoxyquinolines IIaj. The reaction can be carried out in an aqueous solutionof hydrobromic acid by heating under reflux for 2 days.

IIam can be prepared by reaction of IIak with bromides XV. When L⁷ ispyridin-2-yl, the reaction can be carried out in the presence of a metalcatalyst such as Copper(I) iodide with a ligand such asN,N′-dimethylcyclohexane-1,2-diamine and with a suitable base such aspotassium carbonate in a suitable solvent such as 1,2-dimethoxyethane at120° C. for 1 hours under microwave irradiation. When L⁷ is substitutedalkyl such as hydroxyethyl or methoxyethyl, the reaction can be carriedout in the presence of a suitable base such as potassium carbonate in asuitable solvent such as acetone at room temperature overnight.

Compounds of interest Iai and Iaj can be prepared by coupling of IIakand IIam with propane-1,3-diamine separately. The reaction can becarried out at 150° C. for 1.5 hours under microwave irradiation.

General Synthetic Route for Formula Iak (Scheme 10)

Compounds of interest Iak can be prepared according to Scheme 10.Coupling of 4-halogen quinolines IIae withC-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine followed by deprotectionaffords 4-(2,3-diol-propylamino)-quinolines Iak.

IIan can be obtained by coupling of 4-halogen quinolines IIae withC-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine. The reaction can becarried out in analogy to coupling of 4-halogen quinolines IIab withvarious amines XI in Scheme 5. Typically the reaction can be carried outby heating a mixture of 4-halogen quinolines IIae andC-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine at 160° C. for 16 hours.

4-(2,3-Diol-propylamino)-quinolines Iak can be prepared by deprotectionof IIan. The reaction can be carried out in the presence of an acid suchas hydrochloric acid in a suitable solvent such as methanol, ethanol,water or mixtures thereof at room temperature for several hours.

General Synthetic Route for Formula Ial (Scheme 11)

Compounds of interest Ial can be prepared according to Scheme 11.Coupling of fluorides IIao with amines XVI followed by debenzylationaffords compounds of interest Ial.

Quinolines IIap can be prepared from coupling of fluorides IIao (whichcan be prepared in analogy to 4-benzyl diamino quinolines IIaa in Scheme4) with amines XVI. The reaction can be carried out by heating a mixtureof fluorides IIao and amines XVI with a suitable solvent such asN,N-dimethyl formamide, N,N-dimethyl acetamide,N-methyl-2-pyrrolidinone, dimethyl sulfoxide or the mixtures thereof, orwithout any solvent at a temperature between 100° C. and 150° C.,typically at 120° C. under microwave irradiation for several hours.

Compounds of interest Ial can be prepared by standard benzyldeprotection of IIap. The reaction can be carried out in analogy todebenzylation of IIaa in Scheme 4.

General Synthetic Route for Formula IIam and Ian (Scheme 12)

Compounds of interest Iam and Ian can be prepared according to Scheme12. Demethylation of IIaq affords IIar. Coupling of IIar withiodobenzene affords 4-phenoxy benzothiazepines IIas. Coupling of Haswith (3-aminomethyl-oxetan-3-yl)-dibenzylamine followed by debenzylationprovides 4-[(3-amino-oxetan-3-ylmethyl)-amino]quinolines Iam. Couplingof IIar with 3-bromo-propan-1-ol affords IIau. Coupling of 4-halogenquinolines IIau with carbamic acid tert-butyl ester followed bydeprotection of tert-butyloxycarbonyl affords 4-amino quinolines Ian.

IIar can be prepared by demethylation of IIaq. The reaction can becarried out by treating IIaq with a suitable Lewis acid such astribromoborane, aluminum chloride, aluminum bromide, and stannouschloride in a dry organic inert solvent such as dichloromethane,chloroform, acetonitrile and N,N-dimethylformamide at a temperaturebetween 0 and 80° C., typically at 0° C., for a period of 5 minutes to 3hours, typically for 1 hour.

IIas can be obtained by coupling of IIar with iodobenzene. The reactioncan be carried out by heating in the presence of copper(I) iodide orcopper(I) bromide, with a ligand such as N,N-dimethylglycinehydrochloride, (2-pyridyl)acetone or 1,1,1-tris(hydroxymethyl)ethane,and a base such as cesium carbonate, potassium carbonate, or potassiumphosphate, in an organic solvent such as dimethyl sulfoxide,N,N-dimethylformamide, acetonitrile or 1,4-dioxane at a temperaturebetween 80° C. and 120° C. for 4 to 24 hours. Typically, the reactioncan be carried out by heating in the presence of copper(I) iodide,N,N-dimethylglycine hydrochloride and potassium carbonate in dimethylsulfoxide at 120° C. for 6 hours.

Iam can be obtained by coupling of IIas with(3-aminomethyl-oxetan-3-yl)-dibenzylamine followed by debenzylation. Thereactions can be conducted in analogy to preparation of Iaa from IIab inScheme 4. Typically, coupling of IIas with(3-aminomethyl-oxetan-3-yl)-dibenzylamine can be carried out in thepresence of bis(diphenylphosphino)-ferrocenedichloropalladium(II),1,1′-bis(diphenylphosphino)-ferrocene and sodium-tert-butoxide in1,4-dioxane at 120° C. for 2 hours under microwave irradiation.Debenzylation of IIat can be achieved by stirring a solution of IIat inmethanol in the presence of palladium hydroxide on carbon andtrifluoroacetic acid at room temperature under 2 bar of hydrogenatmosphere for 14 hours.

IIau can be prepared by coupling of IIar with 3-bromo-propan-1-ol. Thereaction can be carried out with a suitable base such as potassiumcarbonate, cesium carbonate, sodium tert-butoxide, potassiumtert-butoxide, sodium hydride or 1,8-diazabicyclo[5.4.0]undec-7-ene inan inert organic solvent such as dichloromethane, N,N-dimethylformamide,dimethyl sulfoxide or 1-methyl-pyrrolidin-2-one at a temperature betweenroom temperature and 100° C., typically at 70° C. for several hours.

IIav can be prepared by coupling of 4-halogen quinolines IIau withcarbamic acid tert-butyl ester. The reaction can be carried out in thepresence of a palladium catalyst in analogy to coupling of 4-halogenquinolines IIab with various amines XI in Scheme 5. Typically thereaction can be carried out by heating a mixture of 4-halogen quinolinesIIau and carbamic acid tert-butyl ester in the presence ofbis(diphenylphosphino)ferrocenedichloropalladium(II), with1,1′-bis(diphenylphosphino)ferrocene and sodium-tert-butoxide in1,4-dioxane at 120° C. for 2 hours.

4-Amine quinolines Ian can be obtained by standard deprotection oftert-butyloxycarbonyl of IIav. The reaction can be carried out bytreating IIav with a suitable acid such as hydrochloric acid,trifluoroacetic acid, or sulfuric acid in a suitable solvent such asmethanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or themixtures thereof at a temperature between 0° C. and room temperature for30 minutes to several hours. Typically the reaction can be carried outby treating IIav with trifluoroacetic acid in dichloromethane at roomtemperature for 6 hours.

General Synthetic Route for Formula Iao (Scheme 12)

Compounds of interest Iao can be prepared according to Scheme 13.Coupling of 4-halogen quinolines IIab with various amino acids XVIIgives acids IIaw. Esterification of acids IIaw followed by aminolysisaffords amides Iao.

Acids IIaw can be prepared by coupling of 4-halogen-quinolines IIab withamino acids XVII. The reaction can be carried out in phenol, preferablyat 150° C. in a sealed tube overnight.

Esters IIax can be prepared by esterification of carboxylic acids IIaw.The reaction can be carried out by heating IIaw and methanol in thepresence of a suitable catalyst such as concentrated sulfuric acid, dryhydrochloride gas, or thionyl chloride for several hours. Typically thereaction can be carried out by heating IIaw and methanol in the presenceof thionyl chloride under reflux for 2 hours.

Amides Iao can be prepared by aminolysis of methyl esters IIax. Thereaction can be carried out by heating methyl esters IIax with variousconcentrated amines in alcohol, such as 7N ammonia in methanol or 33%(wt %) methyl amine in absolute ethanol. The reaction can be preferablycarried out at 85° C. in a sealed tube overnight.

General Synthetic Route for Formula Iap (Scheme 14)

Compounds of interest Iap can be prepared according to Scheme 14.Coupling of 4-halogen quinolines IIab with4-aminomethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butylester affords IIay. Cleavage of tert-butyloxycarbonyl and acetalgenerates amino alcohols Iap.

Oxazolidines can be prepared by coupling of 4-halogen quinolines IIabwith 4-aminomethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butylester. The reaction can be carried out in the presence of a palladiumcatalyst in analogy to coupling of 4-halogen quinolines IIab withvarious amines XI in Scheme 5. Typically the reaction can be carried outby heating a mixture of 4-halogen quinolines IIab and4-aminomethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butylester in the presence ofbis(diphenylphosphino)ferrocenedichloropalladium(II), with1,1′-bis(diphenylphosphino)ferrocene and sodium-tert-butoxide in1,4-dioxane at 120° C. for 1.5 hours.

Amino alcohols Iap can be prepared by acid catalyzed cleavage oftert-butyloxycarbonyl and acetal of acetonides IIay. The reaction istypically carried out in a solution of hydrochloride in ethyl acetatefor several hours at room temperature.

General Synthetic Route for Formula Iar (Scheme 15)

Compounds of interest Iar can be prepared according to Scheme 15.Starting with amino alcohols Iaq (prepared in analogue to Idj in Scheme56), ring closure with cyanogen bromide gives oxazoles Iar. The reactioncan be carried out with a suitable base such as sodium acetate, sodiumcarbonate, potassium acetate or potassium carbonate, in a suitablesolvent such as methanol, water, or the mixtures thereof, typically at0° C., followed by stirring at room temperature for several hours.

General Synthetic Route for Formula Iat (Scheme 16)

Compounds of interest Iat can be prepared according to Scheme 16.Starting with amino alcohols Ias (prepared in analogue to Iap in Scheme14 and Iaf in Scheme 7), cyclization with cyanogen bromide affordsoxazoles Iat. Compounds of interest Iat can be prepared by cyclizationof amino alcohols Ias with a slight excess of cyanogen bromide. Thereaction can be carried out in the presence of a suitable base such assodium acetate, sodium carbonate, potassium acetate or potassiumcarbonate, in a suitable solvent such as methanol, water, or themixtures thereof, typically at 0° C., followed by stirring at roomtemperature for several hours.

General Synthetic Route for Formula Iau (Scheme 17)

Compounds of interest Iau can be prepared according to Scheme 17.Starting with IVb, oxidation of IVb gives sulfones IVh, which wascoupled with 2-aminobenzonitriles XVIII to afford imines IIaz. Ringclosure of imines IIaz gives 4-amino quinolines Iau.

Sulfones IVh can be prepared by oxidation of IVb. The reaction can becarried out with a suitable oxidant such as 3-chloroperoxybenzoic acid,hydrogen peroxide, sodium periodate or potassium permanganate, in asuitable solvent such as dichloromethane, acetic acid, water or themixtures thereof, typically at 0° C., followed by stirring at roomtemperature for several hours.

Imines IIaz can be prepared by heating a mixture of IVh,2-aminobenzonitriles XVIII and phosphorous oxychloride. The reaction canbe carried out in a suitable inert organic solvent such asdichloromethane, chloroform or the mixtures thereof, typically at 0-10°C., followed by stirring at reflux for 24 hours.

Compounds of interest Iau can be prepared by ring closure of iminesIIaz. The reaction can be achieved by treatment of IIaz with Lewis acidsuch as zinc chloride in N,N-dimethylacetamide at 120-180° C. forseveral hours in an inert atmosphere.

General Synthetic Route for Formula Iav and Iaw (Scheme 18)

Compounds of interest Iaw and Iav can be prepared according to Scheme18. Staring from 4-amino quinolines Iae, acylation of Iae with acylchlorides XIX gives amides IIba. Reaction of IIba with methanol affordsmethyl ethers Iav. Reaction of IIba with sodium azide followed byhydrogenation of azides generates compounds of formula Iaw.

Amides IIba can be prepared from 4-amino quinolines Iae by acylationwith acy chlorides XIX. The reaction can be carried out with a suitablebase such as potassium carbonate, cesium carbonate, sodium hydride or1,8-diazabicyclo[5.4.0]undec-7-ene in an inert organic solvent such asdichloromethane, tetrahydrofuran or N,N-dimethylformamide, typically atroom temperature, followed by stirring at 50-100° C. for several hours.

Methyl ethers Iav can be prepared by reaction of IIba with methanol. Thereaction can be realized by refluxing IIba in methanol in the presenceof ethylamine overnight.

Azides IIbb can be prepared by reaction of amides IIba with sodiumazide. The reaction can be carried out in a suitable solvent such asacetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, water ormixtures thereof, typically at 25-70° C. for several hours.

Amines Iaw can be prepared by hydrogenation of azides IIbb. The reactioncan be carried out in the presence of 10% palladium on carbon underhydrogen atmosphere in an organic solvent such as ethyl acetate,methanol, or ethanol, typically at room temperature for several hours.

General Synthetic Route for Formula Iax and Iay (Scheme 19)

Compounds of interest Iax and Iay can be prepared according to Scheme19. Starting from 4-aminoquinolines Iae, acylation of Iae with acylchlorides XX gives IIbc. Cleavage of phthalic protecting group from IIbcgenerates amides Iax. Reduction of amides of Iax generates Iay.

IIbc can be prepared by acylation of 4-aminoquinolines Iae. The reactioncan be carried out by stirring a mixture of Iae and acyl chlorides XXwith a suitable base such as N,N-diisopropylethylamine or cesiumcarbonate, in a suitable organic solvent such as dichloromethane,N,N-dimethylformamide or the mixtures thereof, at room temperature forseveral hours.

Amides Iax can be prepared by cleavage of phthalic protecting group fromIIbc. The reaction can be carried out with a suitable base such ashydrazine, hydrazine acetate or low alkyl amine such as methylamine orn-butylamine in an alcohol solvent such as methanol or ethanol at atemperature between room temperature and 90° C. for several hours.Typically, the reaction can be carried out by heating IIbc withmethylamine in ethanol, at 90° C. for 2 hours. Iay can be obtained byreduction of amides of Iax. The reaction can be carried out by heatingIax in a solution of borane-methyl sulfide complex in diethyl ether at80° C. for several hours.

General Synthetic Route for Formula Iba (Scheme 20)

Compounds of interest Iba can be prepared according to Scheme 20.Starting with amines Iaz (prepared in analogue to Iac in Scheme 5 andIaf, Iag in Scheme 7), reductive amination with various aldehydes orketones provides substituted amines Iba when L¹⁶ is ethyl oroxetan-3-yl; coupling of amines Iaz with 2-bromo-pyridine generates Ibawhen L¹⁶ is pyridine-2-yl.

Compounds of interest Iba can be prepared by reductive amination of Iazwith various aldehydes or ketones. This reaction can be carried out witha suitable reducing agent such as sodium triacetoxyborohydride or sodiumcyanoborohydride in a suitable organic solvent such as dichloromethane,1,2-dichloroethane, tetrahydrofuran, methanol or the mixtures thereof,typically with the addition of molecular sieves or acetic acid, at atemperature between room temperature and 70° C. for 2 to 12 hours.

Compounds of interest Iba can also be prepared by coupling of amines Iazwith 2-bromo-pyridine. The reaction is typically performed inN-methylpyrrolidinone with tri(dibenzylideneacetone)dipalladium(0),4,5-bis(diphenylphosphino)-9,9-dimethylxanthe, cesium carbonate at atemperature between 100° C. and 150° C. for several hours under inertatmosphere.

General Synthetic Route for Formula Ibb (Scheme 21)

Compounds of formula Ibb can be prepared as shown in Scheme 21. UreasIbb can be prepared by reaction of 4-amino-quinolines Iae withisocyanides XXI. The reaction can be carried out by stirring4-amino-quinolines Iae with various isocyanide XXI in the presence of asuitable base such as triethylamine in an organic solvent such astetrahydrofuran at a temperature between 0° C. to 50° C. for severalhours.

General Synthetic Route for Formula Ibc (Scheme 22)

Compounds of interest of formula Ibc can be prepared according to Scheme22. Reaction of bromides IIbd with various organoboronic acids orvarious organometallic reagents affords compounds IIbe. Coupling of IIbewith propane-1,3-diamine affords compounds of interest of formula Ibc.

Compounds IIbe can be prepared from reaction of bromides IIbd withvarious organoboronic acids or various metal reagents such as zinccyanide or organostannic reagents. Reaction of bromides IIbd withvarious organoboronic acids can be carried out in the presence of apalladium catalyst such as tetra(triphenylphosphino)palladium orpalladium acetate with a phosphine ligand such as2,2′-bis(diphenylphosphino)-1,1′-binaphthalene and a base such aspotassium carbonate in a suitable solvent such as toluene at 90° C. for16 hours under argon atmosphere. Reaction of bromides IIbd with variousorganometallic reagents can be carried out in the presence of apalladium catalyst such as tetra(tri-phenylphosphino)palladium in asuitable solvent such as N,N-dimethylformamide under reflux for 1 to 2hours under argon atmosphere.

Coupling of halogens IIbe with propane-1,3-diamine can be carried out inanalogy to coupling of 4-halogen quinolines IIab with various amines XIin Scheme 5. Typically, the reaction can be carried out with a palladiumcatalyst such as bis(diphenylphosphino)ferrocenedichloropalladium(II),with a phosphine ligand such as 1,1′-bis(diphenylphosphino)ferrocene,and a suitable base such as sodium-tert-butoxide in a suitable solventsuch as 1,4-dioxane, heated at 120° C. for 2 hours under microwaveirradiation.

General Synthetic Route for Formula Ibd, Ibe and Ibf (Scheme 23)

Compounds of interest Ibd, Ibe and Ibf can be prepared according toScheme 23. Hydrolysis of 2,4-dichloro-quinozalines IIIb affords2-chloro-4-hydroxy-quinozalines Inc. Coupling of2,4-dichloro-quinozalines IIIb with various amines XI affords IIbf.Coupling of IIIc with benzoazapines IVi followed by coupling withvarious amines XI affords compounds of interest Ibd. Coupling of IIbfwith benzoazapines IVi affords compounds of interest Ibd. Coupling ofIIbf with benzothioazapines IVf affords compounds of interest Ibe.Oxidation of sulfides of Ibe affords compounds of interest Ibf.

2-Chloro-4-hydroxy-quinozalines IIIc can be prepared by hydrolysis of2,4-dichloro-quinozalines IIIb. The reaction can be carried out in thepresence of a suitable base such as sodium hydroxide in a suitablesolvent such as tetrahydrofuran, water or mixtures thereof at roomtemperature for several hours.

4-Hydroxy quinozalines IIbg can be prepared by coupling of IIIc withbenzoazapines IVi. The reaction can be carried out in the presence of asuitable base such as triethylamine in a suitable solvent such astoluene or N,N-dimethylformamide at a temperature between 110° C. and160° C. under microwave irradiation for 30 minutes to 2 hours.Alternatively, the reaction can be carried out at an elevatedtemperature such as under reflux overnight without microwaveirradiation.

2-Chloro-4-amino quinozalines IIbf can be prepared by coupling of IIIbwith various amines XI. The reaction can be carried out in the presenceof a suitable base such as triethylamine in a suitable solvent such asmethanol, tetrahydrofuran, dichloromethane or mixtures thereof at atemperature between 0° C. to room temperature for several hours.

Compounds of interest Ibd can be prepared by coupling of IIbg withvarious amines XI. The reaction can be carried out in the presence of asuitable base such as 1,8-diazabicyclo[5.4.0]undec-7-ene with a suitablecoupling reagents such asbenzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate,in a suitable solvent such as N,N-dimethylformamide at room temperaturefor several hours.

Alternatively, compounds of interest Ibd can be obtained by the couplingof IIbf with benzoazapines IVi. The reaction can be carried out with orwithout a base such as triethylamine, in a suitable solvent such asn-butanol or N,N-dimethylformamide at a temperature between 130° C. and160° C. for 30 minutes to several hours under microwave irradiation.Alternatively, this reaction can be carried out with triethylamine inn-butanol in a sealed tube at a lower temperature for several hours,typically at 100° C. for 4 hours.

Compounds of interest Ibe can be prepared by coupling of IIbf withbenzothioazapines IVf. The reaction can be carried out without any baseor with a suitable base such as triethylamine in a suitable solvent suchas n-butanol or N,N-dimethylformamide at a temperature between 130° C.and 160° C. for several hours under microwave irradiation.

Compounds of interest Ibf can be prepared by oxidation of Ibe. Thereaction can be carried out with 3-chloroperoxybenzoic acid indichloromethane or oxone in a mixture solvent such as methanol andtetrahydrofuran at a temperature between 0° C. and room temperature forseveral hours.

General Synthetic Route for Formula Ibj (Scheme 24)

Compounds of interest Ibj can be prepared according to Scheme 24.Starting with Ibh (prepared in analogue to Ibe in Scheme 23), oxidationwith a suitable oxidant provides Ibi. Subsequent debenzylation generatesamines Ibj.

Ibi can be prepared by oxidation of Ibh. The reaction can be carried outwith a suitable oxidant such as 3-chloroperoxybenzoic acid, hydrogenperoxide, sodium periodate or potassium permanganate, in a suitablesolvent such as dichloromethane, acetic acid, water or the mixturethereof, typically at 0° C., followed by stirring at room temperaturefor several hours.

Compounds Ibj can be prepared by standard debenzylation of Ibi. Thereaction can be carried out with palladium on carbon, palladiumhydroxide on carbon or platinum oxide, typically with an acid such asacetic acid or trifluoroacetic acid in a suitable solvent such asmethanol, ethanol, tetrahydrofuran, ethyl acetate or the mixturesthereof, at room temperature under hydrogen atmosphere for severalhours.

General Synthetic Route for Formula Ibl (Scheme 25)

Compounds of interest Ibl can be prepared according to Scheme 25.Starting with amines Ibk (prepared in analogue to Iac in Scheme 5 andIbf in Scheme 23), acylation with acetic anhydride or acetyl chloridegives acetamides Ibl. The reaction can be carried out with a suitablebase such as triethylamine or pyridine in a suitable inert organicsolvent such as dichloromethane, tetrahydrofuran or pyridine at 0° C.,followed by stirring at room temperature for several hours.

General Synthetic Route for Formula Ibm (Scheme 26)

Compounds of interest Ibm can be prepared according to Scheme 26.Coupling of 4-halogen-quinolines IIab withN-(3-methyl-pyrrolidin-3-yl)-acetamide affords compounds IIbh.Deactylation of IIbh affords compounds of interest Ibm.

Compounds IIbh can be prepared by coupling of 4-halogen-quinolines IIabwith N-(3-methyl-pyrrolidin-3-yl)-acetamide. The reaction can be carriedout in the presence of a metal catalyst or in the absence of a metalcatalyst in analogy to coupling of 4-halogen quinolines IIab withvarious amines XI in Scheme 5. Typically, the reaction can be carriedout with 1,1′-bis(diphenylphosphino)ferrocene,1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II), andsodium-tert-butoxide in 1,4-dioxane at 120° C. for 1.5 hours undermicrowave irradiation.

Compounds of interest Ibm can be prepared by deactylation of IIbh. Thereaction can be carried out in 2 N hydrochloric acid at 100° C. for 16hours.

General Synthetic Route for Formula Ibo (Scheme 27)

Compounds of interest Ibo can be prepared according to Scheme 27.Starting with fluorides Ibn, substitution of fluoro with methoxy groupaffords Ibo. The reaction can be carried out by heating of fluorideswith sodium methoxide in methanol, typically at 100° C. for 20 minutesunder microwave irradiation.

General Synthetic Route for Formula Ibq (Scheme 28)

Compounds of interest Ibq can be prepared according to Scheme 28.Demethylation of methoxybenzenes Ibp affords phenols Ibq. The reactioncan be carried out by heating of Ibp with potassium hydroxide indimethylsulfoxide, typically at 100° C. for 20 minutes under microwaveirradiation.

General Synthetic Route for Formula Ibr and Ibs (Scheme 29)

Compounds of interest Ibr and Ibs can be prepared according to Scheme29. Coupling of 4-chloroquinolines IIbi with 4-amino-3-hydroxy-butyricacid followed by reduction of acids IIbj affords 1,3-diols Ibr. Couplingof 4-chloroquinolines IIbi with 2-methyl-allyllamine followed bydihydroxylation of alkenes IIbk affords 1,2-diols Ibs.

Acids IIbj can be obtained by coupling of 4-chloroquinolines IIbi with4-amino-3-hydroxy-butyric acid. Alkenes IIbk can be obtained by couplingof 4-chloro quinolines IIbi with 2-methyl-allylamine. Coupling reactioncan be carried out by heating 4-chloroquinolines IIbi with amines in asuitable organic solvent such as 1-methyl-2-pyrrolidinone at an elevatedtemperature, typically at 160° C. for 16 hours.

1,3-Diols Ibr can be prepared by reduction of acids IIbj. The reactioncan be carried out by treating acids with sodium borohydride in thepresence of iodine in tetrahydrofuran, typically at 0° C., followed bystirring at room temperature for 16 hours.

1,2-Diols Ibs can be prepared by dihydroxylation of alkenes IIbk. Thereaction can be accomplished by treating alkenes with 4-methylmorpholineN-oxide monohydrate and osmium tetroxide in acetone at room temperaturefor 1 hour.

General Synthetic Route for Formula Ibt (Scheme 30)

Compounds of interest Ibt can be prepared according to Scheme 30.Starting with IIbi, alkylation with methyl iodide followed by couplingwith various amines affords compounds of interest Ibt.

Compounds IIbl can be prepared by alkylation of IIbi with methyl iodide.Preferably, compounds can be obtained by deprotonation of α-H of sulfonefollowed by reaction with methyl iodide. Deprotonation of α-H of sulfonecan be carried out by treating sulfone IIbi with n-butyl lithium intetrahydrofuran at −78° C. under argon atmosphere for 1 hour. Reactionwith methyl iodide can be accomplished by addition of methyl iodide tothe above reaction mixture at −78° C., followed by stirring at roomtemperature overnight.

Compounds of interest Ibt can be prepared by coupling of IIbl withvarious amines. The reaction can be carried out in analogy to couplingof 4-halogen quinolines IIab with various amines XI in Scheme 5. Thereaction preferably can be achieved by heating a mixture of IIbl andvarious amines with or without organic solvent such asN,N-dimethylformamide, 1-methylpyrrolidin-2-one or n-butyl alcohol,under microwave irradiation at 140-160° C. for 1-3 hours.

General Synthetic Route for Formula Ibu, Ibv and Ibw (Scheme 31)

Compounds of interest Ibu, Ibv and Ibw can be prepared according toScheme 31. Coupling of 4-chloroquinolines IIbi withN-(3-amino-oxetan-3-ylmethyl)-2,2,2-trifluoro-acetamide affords Ibu.Standard trifluoroacetyl deprotection of Ibu generates compounds Ibv.Trifluoroacetyl deprotection and hydrolysis of Ibu affords Ibw.

Compounds Ibu can be prepared by coupling of 4-chloroquinolines IIbiwith N-(3-amino-oxetan-3-ylmethyl)-trifluoro-acetamide. The reaction canbe carried out in the presence of a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),(triphenylphosphine)dichloropalladium(II), palladium(II) acetate, ortri(dibenzylideneacetone)dipalladium(0), in combination of a phosphineligand such as bis(diphenylphosphino)ferrocene, tricyclohexylphosphine,or 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, with a suitable basesuch as sodium tert-butoxide, in a suitable inert organic solvent suchas 1,4-dioxane, or N,N-dimethylformamide, at 100-150° C. for 1-3 hoursunder microwave irradiation. Alternatively, the reactions can be carriedout at an elevated temperature such as 100-140° C. for a longer reactiontime without microwave irradiation.

Compounds Ibv can be prepared by standard trifluoroacetyl deprotectionof Ibu. The reaction can be carried out with potassium carbonate, in asuitable solvent such as the mixture of methanol and water, at roomtemperature for several hours.

Compounds Ibw can be prepared by trifluoroacetyl deprotection andhydrolysis of Ibu. The reaction is typically carried out with ammoniasolution in methanol for several hours at room temperature.

General Synthetic Route for Formula Ibx and Iby (Scheme 32)

Compounds of interest Ibx and Iby can be prepared according to Scheme32. Standard coupling of IIab with 5-oxo-pyrrolidine-3-carboxylic acidamide generates IIbm, followed by rearrangement of amides IIbm givesaminopyrrolidines Ibx. Coupling of halogens IIab withpyrrolidine-3-carboxylic acid methyl ester affords compounds IIbn.Conversion of IIbn to acylchlorides IIbo followed by treatment withammonia affords compounds of interest Iby.

Amides IIbm can be prepared by copper-mediated coupling reaction of IIabwith 5-oxo-pyrrolidine-3-carboxylic acid amide. The reaction can becarried out in the presence of a copper source such as copper(I) iodideand a ligand such as 2,2′-bipyridine, L-proline, N,N-dimethyl glycine,ethylene glycol or trans-N,N′-dimethylcyclohexane-1,2-diamine, with asuitable base such as triethylamine, sodium carbonate, potassiumcarbonate, cesium carbonate, sodium tert-butoxide, potassiumtert-butoxide, sodium hydride or 1,8-diazabicyclo[5.4.0]undec-7-ene. Thereaction can be carried out in a suitable organic solvent such asdiethylene glycol dimethyl ether, toluene, 1,4-dioxane,N,N-dimethylformamide, dimethyl sulfoxide or 1-methyl-pyrrolidin-2-oneat a temperature between 100° C. and 180° C. for several hours undermicrowave irradiation. Alternatively, the reactions can be carried outat a temperature such as 130° C. for a longer reaction time withoutmicrowave irradiation.

Aminopyrrolidines Ibx can be prepared by rearrangement of amides IIbm.The reaction can be typically carried out in the presence of(diacetoxyiodo)benzene in a mixture of acetonitrile and water forseveral hours at room temperature.

Acids IIbn can be prepared by coupling of halogens IIab withpyrrolidine-3-carboxylic acid methyl ester. The reaction can be carriedout with a suitable base such as diisopropylethylamine without anysolvent at 140° C. for 1.5 hours under microwave irradiation.

Acyl chlorides IIbo can be prepared by chlorination of IIbn. Thereaction can be carried out with such as oxalyl dichloride in thepresence of N,N-dimethylformamide, in a suitable solvent such asdichloromethane at 0° C. to room temperature for 16 hours.

Compounds of interest Iby can be prepared by reaction of IIbo withammonia. The reaction can be carried out in suitable solvent such asdichloromethane at 0° C. to room temperature for 16 hours.

General Synthetic Route for Formula Ibz and Ica (Scheme 33)

Compounds of interest Ibz and Ica can be prepared according to Scheme33. Starting with IIbi, coupling with 2-methylsulfanyl-ethylamine givessulfides IIbp. Selective oxidation of sulfides IIbi gives sulfoxidesIbz. Imination of sulfoxides, followed by hydrolyzation affordscompounds of interest Ica.

Sulfides IIbp can be prepared from coupling of2-benzoazapin-4-chloroquinolines IIbi with 2-methylsulfanyl-ethylamine.The reaction can be carried out in the presence of a palladium catalystin analogy to coupling of 4-halogen quinolines IIab with various aminesXI in Scheme 5. Typically the reaction can be carried out in thepresence of tri(dibenzylideneacetone)dipalladium(0),2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl, andsodium-tert-butoxide in 1,4-dioxane under microwave irradiation at 100°C. for 1.5 hours.

Sulfoxides Ibz can be prepared by oxidation of sulfides IIbp. Thereaction preferably can be carried out with a standard oxidant agentsuch as hydrogen peroxide in a suitable organic solvent such as aceticacid at room temperature for several hours.

Compounds of interest Ica can be prepared by metal-catalyzed iminationof sulfoxides followed by hydrolysis. Imination of sulfoxides can becarried out by treating sulfoxides with rhodium (II) acetate andtrifluoroacetamide or sulfonylamides in combination with iodobenzenediacetate and magnesium oxide in dichloromethane at room temperatureovernight, preferably trifluoroacetamide was used. Hydrolysis can becarried out in the presence of a suitable base, such as potassiumcarbonate, sodium hydroxide or potassium hydroxide in methanol underreflux for 30 minutes to several hours.

General Synthetic Route for Formula Icc (Scheme 34)

Compounds of interest Icc can be prepared according to Scheme 34.Starting with sulfides Icb (prepared in analogue to Iac in Scheme 5),oxidation of sulfides affords compounds of interest Icc.

Compounds of interest Icc can be prepared by oxidation of sulfides Icb.The reaction can be carried out in analogy to oxidation of quinolinesIIac in Scheme 4. Typically the reaction can be carried out by treatingsulfides with potassium permanganate in acetic acid at room temperaturefor 30 minutes to several hours.

General Synthetic Route for Formula Icd (Scheme 35)

Compounds of interest Icd can be prepared according to Scheme 35.Starting with sulfoxides IIbq, metal-catalyzed imination of sulfoxidesfollowed by hydrolysis gives sulfoximines IIbr. Coupling of IIbr withvarious amines affords compounds of interest Icd.

Sulfoximines can be prepared from imination of sulfoxides IIbq followedby hydrolysis. Imination of sulfoxides can be carried out by treatingsulfoxides with rhodium (II) acetate and trifluoroacetamide orsulfonylamides in combination with iodobenzene diacetate and magnesiumoxide in dichloromethane at room temperature overnight, preferablytrifluoroacetamide was used. Hydrolysis can be carried out in thepresence of a suitable base, such as potassium carbonate, sodiumhydroxide, potassium hydroxide or sodium methoxide in methanol underreflux for 30 minutes to several hours.

Compounds of interest Icd can be prepared by coupling of IIbr with1,2-ethylenediamine. The reaction can be carried out in analogy tocoupling of 4-halogen quinolines IIac with various amines XI in Scheme5. Typically the reaction can be carried out with or without an organicsolvent such as N,N-dimethylformamide, 1-methylpyrrolidin-2-one orn-butyl alcohol at a temperature between 140° C. and 160° C. undermicrowave irradiation for 1 to 3 hours.

General Synthetic Route for Formula Ice (Scheme 36)

Compounds of interest Ice can be prepared according to Scheme 36.Oxidation of sulfides IIbs followed by coupling of IIbt withpropane-1,3-diamine affords compounds of interest Ice.

Sulfoxides IIbt can be prepared by oxidation of sulfides IIbs. Thereaction can be carried out with a suitable oxidation reagent such asm-chloroperbenzoic acid in a suitable solvent such as dichloromethane at0° C. for 20 minutes.

Compounds of interest Ice can be prepared by coupling of IIbt withpropane-1,3-diamine. The reaction can be carried out in analogy tocoupling of 4-halogen quinolines IIac with various amines XI in Scheme5. Typically, the reaction can be carried out by treating a mixture ofIIbt and propane-1,3-diamine without any base and without any solvent at150° C. for 1 hour under microwave irradiation.

General Synthetic Route for Formula Icf and Icg (Scheme 37)

Compounds of interest Icg and Icf can be prepared according to Scheme37. Amination of IIbu affords amides IIby. Oxidation of sulfides IIbyaffords sulfones IIbz. Coupling of IIbz with propane-1,3-diamine affordscompounds of interest Icg. Oxidation of sulfides IIbu affords sulfonesIIbv. Reduction of carboxylic acid esters IIbv followed bySwern-oxidation affords aldehydes IIbw. Methylation of IIbw followed bycoupling with propane-1,3-diamine affords compounds of interest Icf.

Amides IIby can be prepared by amination of IIbu. The reaction can becarried out in a solution of ammonia in a suitable solvent such asmethanol, tetrahydrofuran or mixture thereof in a sealed tube at atemperature between 100° C. and 150° C. for several hours, typically at120° C. for 16 hours.

Sulfones IIbz can be prepared by oxidation of sulfides IIby. Thereaction can be carried out in analogy to oxidation of quinolines IIacin Scheme 4. Typically, the reaction can be carried out withm-chloroperbenzoic acid in dichloromethane at 0° C. for 2 hours.

Compounds of interest Icg can be prepared by coupling of IIbz withpropane-1,3-diamine. The reaction can be carried out in analogy tocoupling of 4-halogen-quinolines IIac with various amines XI in Scheme5. Typically, the reaction can be carried out by treating a mixture ofIIbz and propane-1,3-diamine without any base and without any solvent at120° C. for 1 hour under microwave irradiation.

Sulfones IIbv can be prepared by oxidation of sulfides IIbu. Thereaction can be carried out in analogy to oxidation of quinolines IIacin Scheme 4. Typically, the reaction can be carried out withm-chloroperbenzoic acid in dichloromethane at 0° C. for 1 hour.

Aldehydes IIbw can be prepared by reduction of carboxylic acid estersIIbv followed by Swern oxidation. Reduction can be carried out with astandard reducing agent such as sodium boronhydride in a suitablesolvent such as tetrahydrofuran, under reflux for several hours toseveral days, typically 60 hours. Swern oxidation can be carried outwith oxalyl dichloride and dimethyl sulfoxide in the presence oftriethylamine in a suitable solvent such as dichloromethane at −78° C.,then at room temperature for 1 to several hours.

6-(1-Hydroxyethyl)quinolines IIbx can be prepared by methylation ofIIbw. The reaction can be carried out with a methylation reagent such asmethyl magnesium bromide in tetrahydrofuran at a temperature below 12°C. for 10 minutes to several hours.

Compounds of interest Icg can be prepared by coupling of IIbw withpropane-1,3-diamine. The reaction can be carried out in analogy tocoupling of 4-halogen quinolines IIac with various amines XI in Scheme5. Typically, the reaction can be carried out without any metal catalystand without any solvent at 150° C. for 1.5 hours under microwaveirradiation.

General Synthetic Route for Formula Ich and Ici (Scheme 38)

Compounds of interest Ici can be prepared according to Scheme 38.Standard coupling of IIbi with 3-amino-propionitrile generates Ich,cyclization of nitriles with sodium azide affords tetrazoles Ici.

Nitriles Ich can be prepared by coupling reaction of chlorides IIbi with3-amino-propionitrile. The reaction can be carried out in analogy tocoupling of 4-halogen quinolines IIac with various amines XI in Scheme5. Typically, the reaction can be carried out by heating withtri(dibenzylideneacetone)dipalladium(0),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and sodium tert-butoxide intoluene at 110° C. overnight.

Tetrazoles Ici can be prepared by cyclization of nitriles Ich withsodium azide. The reaction can be typically carried out in the presenceof sodium azide and ammonium chloride in N,N-dimethylformamide at atemperature between 60° C. and 100° C., typically at 80° C. for severalhours.

General Synthetic Route for Formula Ick (Scheme 39)

Compounds of formula Ick can be prepared according to Scheme 39.Reduction of 6-nitro quinolines Icj generates 6-amino-quinolines Ick.The reaction can be carried out with stannous chloride in methanol underreflux overnight.

General Synthetic Route for Formula Icl (Scheme 40)

Compounds of interest Icl can be prepared according to Scheme 40.Starting with IIbi, coupling with (3-amino-oxetan-3-ylmethyl)-carbamicacid tert-butyl ester gives spiral compounds Icl. This reaction can becarried out in the presence of a palladium catalyst such as(triphenylphosphine)dichloropalladium(II),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),palladium(II) acetate, or tri(dibenzylideneacetone)dipalladium(0), witha phosphine ligand such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,bis(diphenylphosphino)ferrocene, tricyclohexylphosphine, or9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, with a suitable basesuch as sodium tert-butoxide, in a suitable inert organic solvent suchas toluene, dioxane, or N,N-dimethylformamide, at a temperature between100° C. and 150° C. for 1 to 3 hours under microwave irradiation.Alternatively, the reactions can be carried out at a temperature such as100° C. to 140° C. for a longer reaction time without microwaveirradiation.

General Synthetic Route for Formula Icm (Scheme 41)

Compounds of interest Icm can be prepared according to Scheme 41.Coupling of 2,4-dichloroquinazolines IIIb withC-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine affords IIca. Reactionof 2-chloro-4-aminoquinazolines IIca with6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene 5,5-dioxides IVdfollowed by deprotection affords 4-(2,3-diol-propylamino)-quinolinesIak.

IIca can be obtained by coupling of 2,4-dichloroquinazolines IIIb withC-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine. The reaction can becarried out with a base such as triethylamine in a suitable solvent suchas methanol or dichloromethane at room temperature for several hours.

Intermediates IIcb can be prepared by coupling of 2-chloro-4-aminoquinazolines IIca with 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene5,5-dioxides IVd. The reaction can be carried out in the presence of abase such as triethylamine in N,N-dimethylformamide at a temperaturebetween 120° C. and 180° C., typically at 160° C. for several hours.

4-(2,3-Diol-propylamino)-quinazolines Icm can be prepared bydeprotection of IIcb. The reaction can be carried out in the presence ofan acid such as hydrochloric acid in a suitable solvent such asmethanol, ethanol, water or mixtures thereof at room temperature forseveral hours.

General Synthetic Route for Formula Icn (Scheme 42)

Compounds of interest Icn and Ico can be prepared according to Scheme42. Starting with IIcc, cleavage of tert-butoxycarbonyl gives compoundsof interest Icn. Oxidation of sulfides IIcc generates oxides IIcd,followed by cleavage of tert-butoxycarbonyl generates compounds ofinterest Ico.

IIcd can be prepared by oxidation of thio group of compounds IIcc. Thereaction can be carried out with a suitable oxidant such as oxone,meta-chloroperoxybenzoic acid, hydrogen peroxide, sodium periodate orpotassium permanganate, in a suitable solvent such as methanol,dichloromethane, acetic acid, water or the mixtures thereof, typicallyat 0° C., followed by stirring at room temperature for several hours.

Amines Icn and Ico can be prepared by cleavage of tert-butoxycarbonyl ofIIcc and IIcd respectively. The reaction can be typically carried outwith trifluoroacetic acid in dichloromethane, or hydrogen chloride inmethanol for several hours at room temperature.

General Synthetic Route for Formula Icp (Scheme 43)

Compounds of interest Icp can be prepared according to Scheme 43.Starting with IIce, removal of trifluoroacetyl generates amines Icp. Thereaction can be carried out with potassium carbonate or sodiumhydroxide, in a suitable solvent such as the mixture of ethanol andwater, at room temperature for several hours.

General Synthetic Route for Formula Icq and Icr (Scheme 44)

Compounds of interest Icq and Icr can be prepared according to Scheme44. Starting with quinazolinones IIbg, coupling reaction with aminegives IIcf, followed by cleavage of tert-butoxycarbonyl of IIcf affordscompounds of interest Icq. Starting with quinazolinones IIbg, couplingreaction with amine gives IIcg, followed by cleavage of benzoxycarbonylof IIcg affords compounds of interest Icr.

IIcf and IIcg can be prepared from coupling reaction of IIbg with3-(tert-butoxycarbonyl-amino)pyrrolidine andtrans-3-amino-4-fluoro-pyrrolidine-1-carboxylic acid benzyl esterseparately. The reaction can be carried out in the presence ofbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate,with a suitable base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, ortriethyl amine, in a solvent such as N,N-dimethylformamide oracetonitrile at room temperature overnight.

Compounds of interest Icq can be prepared by standard cleavage oftert-butoxycarbonyl of IIcf. The reaction can be carried out by treatingtert-butyl carbamates IIcf with a suitable acid such as hydrochloricacid, trifluoroacetic acid, or sulfuric acid in a suitable solvent suchas methanol, ethyl acetate, dichloromethane, 1,4-dioxane, water or themixtures thereof at a temperature between 0° C. and room temperature for30 minutes to several hours. Typically the reaction can be carried outby treating tert-butyl carbamates IIaf with trifluoroacetic acid indichloromethane at room temperature for 6 hours.

Compounds of interest Icr can be prepared by cleavage of benzylcarbomates IIcg. The conversion can be achieved by hydrogenolysis orunder strong acidic conditions. Hydrogenolysis of IIcg can be carriedout in the presence of palladium on carbon or palladium black, underhydrogen atmosphere or with a hydrogen donor such as formic acid orammonium formate, in a suitable solvent such as methanol or ethanol, ata temperature between room temperature and 80° C. for 15 minutes toseveral hours. Alternatively the conversion can also be achieved bytreating IIcg under strong acidic conditions such as reflux in 6 Nhydrochloride in methanol for several hours.

General Synthetic Route for Formula Ics (Scheme 45)

Compounds of interest Ics can be prepared according to Scheme 45.Starting with 4-chloro-quinolines IIbi, coupling with(R)-2,2-dimethyl-4-vinyl-oxazolidine-3-carboxylic acid tert-butyl estergives vinyl quinolines IIch. Subsequent reduction and deprotection oftert-butyloxycarbonyl and acetal of IIch generates amino alcohols IIci,which are then cyclized to compounds of interest Ics.

Vinyl quinolines IIch can be prepared by coupling of 4-chloro-quinolinesIIbi with (R)-2,2-dimethyl-4-vinyl-oxazolidine-3-carboxylic acidtert-butyl ester. The reaction can be typically conducted indeoxygenated N,N-dimethylformamide with triethylamine,bis(tri-tert-butylphosphine)palladium(0), at a temperature between 100°C. and 160° C. for several hours under microwave irradiation.Alternatively, the reactions can be carried out at an elevatedtemperature such as between 100 and 140° C. for a longer reaction timewithout microwave irradiation.

Amino alcohols IIci can be prepared from vinyl quinolines IIch byhydrogenolysis and deprotection of tert-butyloxycarbonyl and acetal. Thehydrogenolysis can be carried out in the presence of 10% palladium oncarbon under an atmospheric pressure of hydrogen, in an organic solventsuch as ethyl acetate, methanol, or ethanol, typically at roomtemperature for several hours. Deprotection of acetonides is typicallycarried out in a solution of hydrochloric acid in ethyl acetate forseveral hours at room temperature.

Compounds Ics can be prepared from amino alcohols IIci by ring closurewith cyanogen bromide. The reaction can be carried out with a suitablebase such as sodium acetate, sodium carbonate, potassium acetate orpotassium carbonate, in a suitable solvent such as methanol, water, orthe mixtures thereof, typically at 0° C., followed by stirring at roomtemperature for several hours.

General Synthetic Route for Formula Ict, Icu and Icv (Scheme 46)

Compounds of interest Ict, Icu and Icv can be prepared according toScheme 46. Starting with 4-chloro quinolines IIbi, coupling with ethylacrylate gives alkenes IIcj. Reduction of alkenes IIcj followed byhydrolysis of esters affords compounds of interest Ict. Heck reactioncoupling with acrylonitrile gives alkenes IIck. Hydrogenation of alkenesfollowed by hydrolysis of nitriles affords amides Icu. Alternatively,amides Icu can be formed by aminolysis of esters IIcj. Reduction ofamides Icu affords compounds of interest Icv.

Alkenes IIcj and IIck can be prepared by Heck coupling of4-chloro-quinolines IIbi with ethyl acrylate and acrylonitrileseparately. The reaction can be typically conducted in the presence ofbis(tri-tert-butylphosphine)palladium(0) with triethylamine indeoxygenated N,N-dimethylformamide, at a temperature between 100° C. and160° C. for 30 minutes to several hours under microwave irradiation.Alternatively, the reactions can be carried out at an elevatedtemperature such as between 100° C. and 140° C. for a longer reactiontime without microwave irradiation.

Compounds of interest Ict can be prepared by reduction of alkenes IIcjfollowed by hydrolysis. Reduction can be achieved by treating alkenesIIcj with 2-nitrobenzenesulfonylhydrazide in the presence oftriethylamine in dichloromethane at room temperature for several hours.Hydrolysis can be carried out with a suitable base, such as lithiumhydroxide, or sodium hydroxide in a mixture of water and organicsolvent, such as tetrahydrofuran or methanol at room temperature forseveral hours.

Amides Icu can be prepared by hydrogenation of alkenes IIck followed byhydrolysis of nitriles. Hydrogenation reaction can be carried out in thepresence of palladium on carbon under hydrogen atmosphere in methanol atroom temperature for several hours. Hydrolysis can be achieved bytreating nitriles with a base such as potassium hydroxide intert-butanol under reflux for several hours.

Alternatively, amides Icu can be prepared by aminolysis of esters IIcj.The reaction can be typically conducted in an ammonia solution intetrahydrofuran at a temperature between 25° C. to 70° C. for severalhours.

Amines Icv can be prepared by reduction of amides Icu. The reaction canbe achieved by treating amides Icu with borane in tetrahydrofuran at anelevated temperature such as 65° C. for several hours.

General Synthetic Route for Formula Icw and Icx (Scheme 47)

Compounds of interest Icw and Icx can be prepared according to Scheme47. Coupling of 4-halogen quinolines IIab withN-(2-hydroxyethyl)acetamide followed by deacylation of IIcl affordscompounds of interest Icw. Coupling of IIab with protected alcohol XXIIfollowed by cleavage of tert-butyloxycarbonyl affords compounds ofinterest Icx.

Ethers IIcl and IIcm can be prepared by coupling of 4-halogen quinolinesIIab with N-(2-hydroxyethyl)acetamide and XXII separately. The reactioncan be carried out with a palladium catalyst such as1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride incombination with 1,1′-bis(diphenylphosphino)ferrocene and sodiumtert-butoxide in a suitable organic solvent such as 1,4-dioxane in asealed microwave process vial at an elevated temperature such as 130° C.under microwave irradiation for 1 to several hours.

2-Aminoethyl ethers Icw can be prepared by deacylation of IIcl. Thereaction can be carried out in an aqueous solution of hydrochloric acidat an elevated temperature such as 80° C. for several hours.

Compounds of interest Icx can be prepared by cleavage oftert-butyloxycarbonyl. The reaction can be carried out withtrifluoroacetic acid in dichloromethane or hydrochloride in ethylacetate at room temperature for several hours.

General Synthetic Route for Formula Icy (Scheme 48)

Compounds of interest Icy can be prepared according to Scheme 48.Starting with 2,4-dichloro-quinolines IIId, regioselective nucleophillicreplacement with diethyl malonate followed by hydrolysis affordscarboxylic acids IIco. Coupling of IIco with benzothiazepines anddecarboxylation in a tandem reaction affords 4-methyl-quinolines IIcp.Oxidation of sulfides IIcp affords sulfones Icy.

IIcn can be prepared from regioselective nucleophillic replacement withdiethyl malonate. The reaction can be carried out in the presence of asuitable base such as sodium hydride or potassium carbonate, in anorganic solvent such as N,N-dimethylformamide, at an elevatedtemperature, typically at 70° C. for several hours to overnight.

Carboxylic acids IIco can be prepared from hydrolysis of IIcn. Thereaction can be carried out with a suitable base such as lithiumhydroxide or sodium hydroxide in a suitable mixed solvent such astetrahydrofuran and water or methanol and water, at room temperature forseveral hours.

IIcp can be obtained by coupling of 2-chloroquinolines IIco withbenzothiazepines and decarboxylation in a tandem reaction. The reactionpreferably can be carried out with or without an organic solvent such asn-butanol under microwave irradiation at a temperature between 150° C.and 170° C. for several hours.

Compounds of interest Icy can be prepared by oxidation of IIcp. Thereaction can be carried out in analogy to oxidation of quinolines IIacin Scheme 4.

General Synthetic Route for Formula Icz (Scheme 49)

Compounds of interest Icz can be prepared according to Scheme 49.Starting with 4-bromoquinolines IIcq, reaction with a lithium alkylidefollowed by reaction with 1-tert-butoxycarbonyl-4-piperidinecarboxaldehyde provides the secondary alcoholsIIcr. Dess-Martin oxidation of IIcr followed by cleavage of tert-butylcarbamates affords compounds of interest Icz.

IIcr can be obtained by reaction of 4-bromoquinolines IIcq with alithium alkylide followed by reaction with1-tert-butoxycarbonyl-4-piperidinecarboxaldehyde. The conversion can beachieved by treating 4-bromo-quinolines IIcq with n-butyllithium and1-tert-butoxycarbonyl-4-piperidinecarboxaldcehyde in an inert organicsolvent such as tetrahydrofuran at −78° C., then at room temperatureovernight.

Compounds of interest Icz can be obtained by Dess-Martin oxidation ofIIcr followed by cleavage of tert-butyl carbamates. Oxidation of IIcrcan be carried out with a suitable oxidant such as Dess-martin reagentin dichloromethane at room temperature overnight, or with manganesedioxide in toluene under reflux for several hours. Cleavage oftert-butyl carbamates can be achieved by treating tert-butyl carbamatesIIcs with a suitable acid such as hydrochloric acid, trifluoroaceticacid, or sulfuric acid in a suitable solvent such as methanol, ethylacetate, dichloromethane, 1,4-dioxane, water or the mixture thereof at atemperature between 0° C. and room temperature for 30 minutes to severalhours. Typically the reaction can be carried out by treating tert-butylcarbamates IIcs with trifluoroacetic acid in dichloromethane at roomtemperature for 6 hours.

General Synthetic Route for Formula Ida (Scheme 50)

Compounds of interest Ida can be prepared according to Scheme 50.Coupling of bromides IIct with 1H-pyrazole-3-boronic acid affords Ida.The reaction can be carried out in the presence of a palladium catalystsuch as (triphenylphosphine)palladium with sodium carbonate in asuitable organic solvent such as benzene or dimethoxyethane, at atemperature between 80° C. and 120° C., typically at 80° C. for 1 hourunder microwave irradiation

General Synthetic Route for Formula Ida (Scheme 51)

Compounds of interest Idb and Idc can be prepared according to Scheme51. Coupling of chlorides IIbi with benzenethiol affords IIcu. Oxidationof IIcu affords compounds of interest Idb. Coupling of chlorides IIbiwith sodium methanethiolate affords IIcv. Oxidation and chlorination ofIIcv affords sulfonyl chlorides IIcw. Coupling of sulfonyl chloridesIIcw with ethyl-1,2-diamine affords compounds of interest Idc.

Compounds of interest of formula IIcu can be prepared by coupling ofchlorides IIbi with benzenethiol. The reaction can be carried out with asuitable base such as N,N-dimethylpyridin-4-amine in a suitable solventsuch as ethanol at room temperature for several days.

Sulfones Idb can be prepared by oxidation of IIcu. The reaction can becarried out with a suitable oxidation reagent such as m-chloroperbenzoicacid in a suitable solvent such as dichloromethane at a temperaturebetween 0° C. and room temperature for 1 to several hours.

Thiols IIcv can be prepared by coupling of chlorides IIbi with sodiummethanethiolate. The reaction can be carried out in a suitable solventsuch as N,N-dimethylformamide under reflux overnight.

Sulfonyl chlorides IIcw can be prepared by oxidation-chlorination ofIIcv. The reaction can be carried out in a suitable solvent such ashydrochloric acid by bubbling of chlorine at a temperature between 0° C.and 10° C. for 30 minutes.

Compounds of interest Idc can be prepared by coupling of chlorides IIcwwith ethyl-1,2-diamine. The reaction can be carried out with a suitablebase such as triethylamine or ethyl-diisopropyl-amine in a suitablesolvent such as dichloromethane at a temperature between 0° C. and roomtemperature overnight.

General Synthetic Route for Formula Idd, Ide and Idf (Scheme 52)

Compounds of interest Idd, Ide and Idf can be prepared according toScheme 52. Coupling of chlorides IIbv withC-(3-aminomethyl-oxetan-3-yl)-methylamine generates Idd. Hydrolysis ofesters affords carboxylic acids Ide. Reduction of esters IIbv followedby coupling with C-(3-aminomethyl-oxetan-3-yl)-methylamine generatescompounds Idf.

Compounds Idd can be prepared by coupling of chlorides IIbv withC-(3-aminomethyl-oxetan-3-yl)-methylamine. The reaction can be carriedin analogy to coupling of 4-halogen quinolines IIab with various aminesXI in Scheme 5. Typically the reaction can be carried out withtris(dibenzylideneacetone)dipalladium(0),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and sodium tert-butoxide intoluene at 110° C. overnight under nitrogen atmosphere.

Acids Ide can be prepared from hydrolysis of methyl esters Idd. Thereaction can be carried out with a suitable base such as sodiumhydroxide or lithium hydroxide in a mixture solvent of tetrahydrofuranand water at a temperature between room temperature and 60° C.,typically at room temperature for several hours or overnight.

Hydroxides IIcx can be prepared by reduction of esters IIbv. Thereaction can be carried out with a standard reduction agent such aslithium aluminium hydride in a suitable solvent such as tetrahydrofuran,at a temperature between 0° C. and room temperature for several hours,typically at room temperature for 2 hours.

Compounds Idf can be prepared by coupling of IIcx withC-(3-aminomethyl-oxetan-3-yl)-methylamine. The reaction can be carriedout in analogy to coupling of IIbv withC-(3-aminomethyl-oxetan-3-yl)-methylamine in this scheme.

General Synthetic Route for Formula Idg (Scheme 53)

Compounds of interest Idg can be prepared according to Scheme 53.Starting with 2,4-dichloro-quinazolines IIId, reaction with benzylalcohol followed by coupling with benzothiazepines IVf affords benzyloxycompounds IIcz. Substitution of bromo with methyl-d³ followed byoxidation affords 6-methyl-d³-quinazolines IIdb. Coupling of IIdb withC-(3-aminomethyl-oxetan-3-yl)-methylamine affords compounds of interestIdg.

2-Chloro-4-benzoxy quinazolines IIcy can be prepared by reaction of2,4-dichloro-quinazolines IIId with benzyl alcohol. The reaction can becarried out in the presence of a suitable base such as sodium hydride inan organic solvent such as tetrahydrofuran, acetonitrile orN,N-dimethylformamide at 0° C. followed by at room temperature forseveral hours.

IIcz can be prepared by coupling of IIcy with benzothiazepines IVf. Thereaction can be carried out without any base and without any solvent ata temperature between 80° C. and 160° C., typically at 80° C. for 10minutes to 2 hours.

6-Methyl-d³-quinazolines IIda can be prepared by substitution of bromowith methyl-d³. The reaction can be carried out by treating IIcy withn-butyllithium in anhydrous tetrahydrofuran at −78° C. for severalminutes under nitrogen followed by stirring with methyl-d³trifluoromethanesulfonate at −78° C. and then at room temperature for 1to several hours.

Sulfoxides IIdb can be prepared by oxidation of IIda. The reaction canbe carried out by treating IIda with 1-2 equivalents of3-chloroperoxybenzoic acid in a suitable organic solvent such asdichloromethane, chloroform, 1,2-dichloroethane or the mixtures thereof,typically at 0° C., followed by stirring at room temperature for 10 to20 minutes.

Compounds of interest Idg can be prepared by coupling of IIdb withC-(3-aminomethyl-oxetan-3-yl)-methylamine. The reaction can be carriedout without any solvent and without any base at an elevated temperaturesuch as 170° C. for 20 minutes.

General Synthetic Route for Formula Idh (Scheme 54)

Compounds of interest Idh can be prepared according to Scheme 54.Starting with 6-bromo-quinazolines IIda, carbonylation followed byesterification, oxidation and hydrolysis affords acids IIde. Coupling ofIIde with C-(3-aminomethyl-oxetan-3-yl)-methylamine generates compoundsof interest Idh.

6-Methoxycarbonyl quinazolines IIdc can be prepared by carbonylation of6-bromo-quinazolines IIda followed by esterification. Carbonylation canbe carried out with dry ice in the presence of n-butyllithium intetrahydrofuran at −78° C. under nitrogen atmosphere, followed bystirring at room temperature for 1 to several hours. Methylesterification can be carried out in methanol in the presence ofsulfinyl chloride or concentrated sulfuric acid at a temperature betweenroom temperature and 70° C. for 1 to several hours

Compounds IIdd can be prepared by oxidation of IIdc. Oxidation can becarried out by treating IIdc with 1-2 equivalent(s) of3-chloroperoxybenzoic acid in a suitable organic solvent such asdichloromethane, chloroform, 1,2-dichloroethane or mixtures thereof,typically at 0° C., followed by stirring at room temperature for 10minutes to several hours.

Acids IIde can be prepared by hydrolysis of methyl esters IIdd. Thereaction can be carried out with a suitable base such as sodiumhydroxide or lithium hydroxide in a mixture of tetrahydrofuran and waterat a temperature between room temperature and 60° C., typically at roomtemperature for several hours or overnight.

Compounds of interest Idh can be prepared by couplin, g of IIde withC-(3-aminomethyl-oxetan-3-yl)-methylamine. The reaction can be carriedout without any solvent and without any base at 170° C. for 30 minutes.

General Synthetic Route for Formula Idi (Scheme 55)

Compounds of Idi can be prepared according to Scheme 55. Starting with6-bromo quinazolines IIda, Bouveault formylation followed by reductionof aldehyde and oxidation of sulfide affords4-benzyloxy-6-hydroxymethyl-quinazolines IIdh. Coupling of IIdh withC-(3-aminomethyl-oxetan-3-yl)-methylamine generates compounds ofinterest Idi.

Aldehydes IIdf can be prepared by Bouveault formylation. The reactioncan be carried out by treating bromide with n-butyllithium in anhydroustetrahydrofuran at −78° C. followed by stirring with anhydrousN,N-dimethylformamide at −78° C. for 30 minutes to several hours.

6-Hydroxymethyl-quinazolines IIdg can be prepared by reduction ofaldehydes. The reaction can be carried out with sodium borohydride in asuitable organic solvent such as methanol, tetrahydrofuran or themixture thereof at 0° C. for 15 minutes to several hours.

IIdh can be prepared by oxidation of sulfides. Oxidation can be carriedout with 1-2 equivalents of 3-chloroperoxybenzoic acid in a suitableorganic solvent such as dichloromethane, chloroform, 1,2-dichloroethaneor mixtures thereof, typically at 0° C., followed by stirring at roomtemperature for 10 minutes to several hours.

Compounds of interest Idi can be prepared by coupling IIdh withC-(3-aminomethyl-oxetan-3-yl)-methylamine. The reaction can be carriedout without any solvent and without any base at 160° C. for 30 minutes.

General Synthetic Route for Formula Idj (Scheme 56)

Compounds of interest Idj can be prepared according to Scheme 56.Starting with 2,4-dihalogen-quinolines IIIa, coupling with benzoazepinesIVi affords 2-benzoazepin-4-halogen-qunolines IIdi. Coupling of IIdiwith various amines generates compounds of interest Idj.

2-Benzoazepin-4-halogen-qunolines IIdi can be prepared by coupling of2,4-dihalogen-quinolines IIIa with benzoazepines IVi. The reaction canbe carried out with or without a solvent such as n-butanol at 160° C.for several hours under microwave irradiation.

Compounds of interest Idj can be prepared by coupling of IIdi withvarious amines. The reaction can be carried out in analogy to couplingof 4-halogen-quinolines IIab with various amines XI in Scheme 5.Typically the reaction can be carried out in the presence of1,1′-bis(diphenylphosphino)ferrocene,1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride and sodiumtert-butoxide in 1,4-dioxane at 120° C. for 1.5 hours under microwaveirradiation.

General Synthetic Route for Formula Idk (Scheme 57)

Compounds of interest Idk can be prepared according to Scheme 57.Starting with IIIc, coupling with1,2,3,4-tetrahydro-benzo[c]azepin-5-one followed by reaction with methylmagnesium bromide affords 5-methyl-5-hydroxy benzothiazepines IIdk.Coupling of IIdk with 3-aminomethyl-oxetan-3-ylamine generates compoundsof interest Idk.

2-Benzoazepin-quinolines IIdj can be prepared by coupling of IIIc with1,2,3,4-tetrahydro-benzo[c]azepin-5-one. The reaction can be carried outin the presence of an organic base such as triethylamine in tolueneunder reflux overnight.

5-Methyl-5-hydroxy benzothiazepines IIdk can be prepared by reaction ofketones IIdj with methyl magnesium bromide. The conversion can beachieved by stirring of IIdj with methyl magnesium bromide intetrahydrofuran at 50° C. for several hours.

Compounds of interest Idk can be prepared by coupling of IIdj with3-aminomethyl-oxetan-3-ylamine. The reaction can be carried out in thepresence of a suitable base such as 1,8-diazabicyclo[5.4.0]undec-7-enewith a suitable phosphine ligand such asbenzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate,in a suitable solvent such as N,N-dimethylformamide at room temperaturefor several hours.

General Synthetic Route for Formula Idl (Scheme 58)

Compounds of interest Idl can be prepared according to Scheme 58.Starting with Mb, reaction with various benzylamino ethylamines XXIIIaffords IIdl. Substitution of 2-chloro with5,5-difluoro-2,3,4,5-tetrahydro-1H-benzo[c]azepine followed bydeprotection of benzyl generates compounds of interest Idl.

2-Chloro-quinazolines IIdl can be prepared by coupling of IIIb withvarious amines XXIII. The reaction can be carried out in the presence ofa suitable base such as triethylamine in a suitable solvent such asmethanol, tetrahydrofuran, dichloromethane or mixtures thereof at atemperature between 0° C. and room temperature for several hours orovernight.

Compounds Idl can be prepared by standard benzyl deprotection of IIdm.The reaction can be carried out with palladium on carbon, palladiumhydroxide on carbon or platinum oxide, typically with addition of aceticacid or trifluoroacetic acid in a suitable solvent such as methanol,ethanol, tetrahydrofuran, ethyl acetate or the mixture thereof, at roomtemperature for several hours under hydrogen atmosphere.

General Synthetic Route for Formula Idm (Scheme 59)

Compounds of interest Idm can be prepared according to Scheme 59.Starting with naphthalen-2-ones XXIV, ring expansion with hydrazoic acidgives benzoazepin-3-ones IVj. Reduction of lactams IVj to benzoazepinesIVk followed by coupling of IVk with 2,4-dihalogen quinolines IIIa gives4-halogen quinolines IIdn. Coupling of IIdn with various amines XIaffords compounds of interest Idm.

Benzoazepin-3-ones IVj can be prepared from ring expansion ofnaphthalen-2-ones XXIV by using sodium azide. The reaction can becarried out in toluene with a suitable acid such astrifluoromethanesulfonic acid, trifluoroacetic acid or hydrochloricacid, typically at 0° C., followed by stirring at room temperature forseveral hours.

Benzoazepines IVk can be prepared from benzoazepin-3-ones IVj byreduction of lactams. The reaction can be carried out with standardreducing agent such as lithium aluminium hydride, boron hydride orcombination of sodium borohydride and boron trifluoride in a suitableinert organic solvent such as tetrahydrofuran, diethyl ether or mixturesthereof, typically at 0° C., followed by stirring at a temperaturebetween 25° C. and 70° C. for several hours.

4-Halogen quinolines IIdn can be prepared from coupling of benzoazepinesIVk and 2,4-dihalogen quinolines IIIa. The reaction can be carried outwith a suitable acid such as hydrochloric acid or p-toluenesulfonic acidin a suitable organic solvent such as toluene, dioxane, n-butyl alcoholor 2-methyl-2-pentanol at a temperature between 100° C. and 120° C. forseveral hours. Alternatively, the reaction can be carried out withoutacid at a temperature between 100° C. and 160° C. for 1 to 3 hours undermicrowave irradiation.

Compounds of interest Idm can be prepared by coupling of 4-halogenquinolines IIdn with various amines XI. The reaction can be achieved bymicrowave irradiation at a temperature between 140° C. and 160° C. for 1to 3 hours with or without organic solvent such asN,N-dimethylformamide, 1-methylpyrrolidin-2-one or n-butyl alcohol.

B. General Synthetic Route for Formula Idm (Scheme 60)

Compounds of interest Idm can be prepared according to Scheme 60.Acylation of benzoazepines IVk, followed by coupling with2-aminobenzonitriles XVIII provides imines IIdo. Ring closure of iminesIIdo gives 4-aminoquinolines IIdp. Sandmeyer reaction of4-aminoquinolines IIdp provides 4-halogen quinolines IIdq. Coupling ofIIdq with various amines XI generates compounds of interest Idm.

Acetyl benzoazepines IVm can be prepared by acylation of benzoazepinesIVk with acetyl chloride or acetic anhydride. The reaction can becarried out with a suitable base such as triethylamine or pyridine in asuitable inert organic solvent such as dichloromethane, tetrahydrofuranor pyridine at 0° C., followed by stirring at room temperature for 30minutes.

Imines IIdo can be prepared by heating a mixture of IVm,2-aminobenzonitriles XVIII and phosphorous oxychloride. The reaction canbe carried out in a suitable inert organic solvent such asdichloromethane, chloroform or the mixtures thereof, typically at atemperature between 0° C. and 10° C., followed by stirring under refluxfor 24 hours.

Ring closure of imines IIdo to give 4-aminoquinolines IIdp can beachieved by treatment of IIdo with Lewis acid such as zinc chloride inN,N-dimethyl-acetamide at a temperature between 120° C. and 180° C. forseveral hours in an inert atmosphere.

Intermediates IIdq can be prepared from 4-aminoquinolines IIdp by usingSandmeyer reaction. The conversion is typically conducted in standardSandmeyer reaction conditions such as sodium nitrite, hydrochloric acidand sodium chloride or copper(I) chloride in a suitable solvent such aswater, typically at −10° C., followed by stirring at room temperaturefor several hours.

Compounds of interest Idm can be prepared by coupling of IIdq withvarious amines XI. The reaction can be achieved by microwave irradiationat a temperature between 140° C. and 160° C. for 1-3 hours with orwithout organic solvent such as N,N-dimethylformamide,1-methyl-pyrrolidin-2-one or n-butyl alcohol.

General Synthetic Route for Formula Idn (Scheme 61)

Compounds of interest Idn can be prepared according to Scheme 61.Starting with 7-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine IVn,copper-catalyzed coupling with sodium sulfinates XXV gives sulfonylsIVo. Coupling of IVo with 2,4-dihalogen quinolines IIIa gives 4-halogenquinolines IIdr. Coupling of IIdr with various amines XI affordscompounds of interest Idn.

The copper-mediated coupling reaction of7-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine IVn with sodium sulfinatesXXV illustrated above can be carried out in the presence of a coppersource such as copper(I) iodide (CuI), and a ligand such as2,2′-bipyridine, L-proline, N,N-dimethyl glycine or ethylene glycol,with a suitable base such as triethylamine, sodium carbonate, potassiumcarbonate, cesium carbonate, sodium tert-butoxide, potassiumtert-butoxide, sodium hydride or 1,8-diazabicyclo[5.4.0]undec-7-ene. Thereaction can be carried out in a suitable organic solvent such asacetonitrile, toluene, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide or 1-methyl-pyrrolidin-2-one at a temperature between 100° C.and 180° C. for 15 to 60 minutes under microwave irradiation.Alternatively, the reactions can be carried out at a temperature such as130° C. for a longer reaction time without the use of microwaveirradiation.

Compounds IIdr can be prepared from coupling of benzoazepine IVo and2,4-dihalogen quinolines IIIa. The reaction can be carried out with asuitable acid such as hydrochloric acid or p-toluenesulfonic acid in asuitable organic solvent such as toluene, dioxane, n-butyl alcohol or2-methyl-2-pentanol at a temperature between 100° C. and 120° C. forseveral hours. Alternatively, the reaction can be carried out withoutacid at a temperature between 100° C. and 160° C. for 1-3 hours undermicrowave irradiation.

Compounds of interest Idn can be prepared by coupling of IIdr withvarious amines XI. The reaction can be achieved by microwave irradiationat 140-160° C. for 1-3 hours with or without organic solvent such asN,N-dimethylformamide, 1-methyl-pyrrolidin-2-one or n-butyl alcohol.

D. General Synthetic Route for Formula Ido (Scheme 62)

Compounds of interest Ido can be prepared according to Scheme 62.Starting with phenols IIds, alkylation with various XXVI provides IIdt.Coupling of IIdt with various amines XI affords compounds of interestIdo.

Compounds IIdt can be prepared by alkylation of phenols lids with XXVI.The reaction can be carried out with a suitable base such as cesiumcarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydrideor 1,8-diazabicyclo[5.4.0]undec-7-ene in an inert organic solvent suchas dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide or1-methyl-pyrrolidin-2-one, typically at room temperature for severalhours.

Compounds of interest Ido can be prepared by coupling of IIdt withvarious amines XI. The reaction can be achieved by microwave irradiationat a temperature between 140° C. and 160° C. for 1 to 3 hours with orwithout organic solvent such as N,N-dimethylformamide,1-methyl-pyrrolidin-2-one or n-butyl alcohol.

F. General Synthetic Route for Formula Idp (Scheme 63)

Compounds of interest Idp can be prepared according to Scheme 63.Starting with IIdu, palladium-catalyzed carbonylation gives carboxylicacid methyl esters IIdv. Basic hydrolysis of esters IIdv to acids IIdwfollowed by coupling with various amines XXVII to furnishes amides IIdx.Coupling of IIdx with various amines XI affords compounds of interestIdp.

Palladium-catalyzed carbonylation of IIdu to the corresponding methylesters IIdv can be accomplished under an atmosphere of carbon monoxide(1 atmospheric pressure) in methanol. The reaction can be carried out inthe presence of a palladium catalyst such asbis(triphenylphosphine)dichloropalladium(II), palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0), ortri(dibenzylideneacetone)dipalladium(0), in the presence or absence of aphosphine ligand such as tricyclohexylphosphine or triphenylphosphine,and a suitable base such as triethylamine, sodium carbonate or potassiumcarbonate at a temperature between 60° C. and 120° C. for several hours.

Hydrolysis of the methyl esters IIdv to acids IIdw can be carried out inthe presence of an aqueous inorganic base such as lithium hydroxide,sodium hydroxide, or potassium hydroxide in a solvent such as methanol,1,4-dioxane or tetrahydrofuran at room temperature for several hours.

Amides IIdx can be prepared by coupling various amines XXVII withcarboxylic acids IIdw. The reaction is typically conducted with standardpeptide coupling reagents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and1-hydroxybenzotriazole,bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate anddiisopropylethylamine, orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate and a base such as triethylamine, ordiisopropylethylamine in a suitable inert solvent such asdichloromethane or N,N-dimethylformamide or mixtures thereof at roomtemperature for several hours.

Compounds of interest Idp can be prepared by coupling of amides IIdxwith various amines XI. The reaction can be conducted by microwaveirradiation at a temperature between 140° C. and 160° C. for 1 to 3hours with or without organic solvent such as N,N-dimethylformamide,1-methyl-pyrrolidin-2-one or n-butyl alcohol.

G. General Synthetic Route for Formula Idq (Scheme 64)

Compounds of interest Idq can be prepared according to Scheme 64.Palladium-catalyzed coupling of lactams IVp with 2,4-dihalogenquinolinesIIIa gives intermediates IIdy. Coupling of IIdy with various amines XIgenerates compounds of interest Idq.

Intermediates IIdy can be prepared from lactams IVp by coupling with2,4-dihhalogenquinolines IIIa. The reaction can be carried out typicallyin the presence of a palladium catalyst such asbis(triphenylphosphine)dichloropalladium(II), palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0), ortri(dibenzylideneacetone)dipalladium(0), in the presence of a phosphineligand such as tricyclohexylphosphine, or9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, with a suitable basesuch as potassium phosphate tribasic, sodium carbonate or potassiumcarbonate, in a suitable inert organic solvent such as dioxane, orN,N-dimethylformamide, at a temperature between 100° C. and 150° C. forseveral hours.

Compounds of interest Idq can be prepared by coupling of IIdy withvarious amines XI. The reaction can be achieved by microwave irradiationat a temperature between 140° C. and 160° C. for 1 to 3 hours with orwithout organic solvent such as N,N-dimethylformamide,1-methyl-pyrrolidin-2-one or n-butyl alcohol.

H. General Synthetic Route for Formula Ids (Scheme 65)

Compounds of interest Ids can be prepared according to Scheme 65.Starting with diamines Idr (prepared in analogue to Idm in Scheme 59 orScheme 60), guanidation with 3,5-dimethyl-1H-pyrazole-1-carboximidamidenitrate gives guanidines Ids. The reaction can be carried out in asuitable solvent such as ethanol, typically at a temperature between 70°C. and 90° C. for several hours.

L. General Synthetic Route for Formula Idt (Scheme 66)

Compounds of interest Idt can be prepared according to Scheme 66.Starting with benzoazepines IVk, coupling with2-chloro-quinoline-4-carboxylic acid methyl ester XXVIII gives compoundsIIdz, which are in turn reduced to compounds of interest Idt.

Esters IIdz can be prepared from benzoazepines IVk by coupling with2-chloro-quinoline-4-carboxylic acid methyl ester XXVIII. The reactioncan be carried out with a suitable acid such as hydrochloric acid orp-toluenesulfonic acid in a suitable organic solvent such as toluene,dioxane, n-butyl alcohol or 2-methyl-2-pentanol at a temperature between100° C. and 120° C. for several hours. Alternatively, the reaction canbe carried out without acid at a temperature between 100° C. and 160° C.for 1 to 3 hours under microwave irradiation.

Alcohols Idt can be prepared from methyl esters IIdz by reduction. Thereaction is typically conducted in a tetrahydrofuran solution of boraneat 0° C., followed by stirring at reflux temperature for several hours.

M. General Synthetic Route for Formulas Idu and Idv (Scheme 67)

Compounds of interest Idu and Idv can be prepared according to Scheme67. Starting with 4-halogen quinolines IIdn, Suzuki reaction couplingwith 2-allyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane gives4-allyl-quinolines IIea and compounds Idv as a byproduct.4-Allyl-quinolines IIea are then converted to compounds of interest Iduby Upjohn dihydroxylation.

4-Allyl-quinolines IIea and compounds Idv can be prepared from 4-halogenquinolines IIdn by Suzuki coupling with2-allyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. The reaction istypically conducted in 1,2-dimethoxyethane and water with potassiumcarbonate, tetrakis(triphenylphosphine)palladium(0), at a temperaturebetween 80° C. and 140° C. for several hours under microwaveirradiation. Alternatively, the reactions can be carried out at a heatedtemperature such as a temperature between 100° C. and 140° C. for alonger reaction time without the use of microwave irradiation.

Compounds of interest Idu can be prepared from 4-allyl-quinolines IIeaby Upjohn dihydroxylation. The reaction can be typically carried out inwater with osmium tetroxide and N-methyl morpholine-N-oxide at roomtemperature for several hours.

P. General Synthetic Route for Formula Idw (Scheme 68)

Compounds of interest Idw can be prepared according to Scheme 68.Starting with diazepines IVq, coupling of 2,4-dihalogen quinolines IIIawith IVq furnishes IIeb. Subsequent coupling of IIeb with various aminesXI generates compounds of interest Idw.

Compounds IIeb can be prepared from coupling of 2,4-dihalogen quinolinesIIIa with diazepines IVq. The reaction can be carried out with asuitable acid such as hydrochloric acid or p-toluenesulfonic acid in asuitable organic solvent such as toluene, dioxane, n-butyl alcohol or2-methyl-2-pentanol at a temperature between 100° C. and 120° C. forseveral hours. Alternatively, the reaction can be carried out withoutacid at a temperature between 100° C. and 160° C. for 1 to 3 hours undermicrowave irradiation.

Compounds of interest Idw can be prepared by coupling of compounds IIebwith various amines XI. The reaction can be carried out typically in thepresence of a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),(triphenylphosphine)dichloropalladium(II), palladium(II) acetate, ortri(dibenzylideneacetone)dipalladium(0), in the presence of a phosphineligand such bis(diphenylphosphino)ferrocene, tricyclohexylphosphine, or9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, with a suitable basesuch as sodium tert-butoxide, in a suitable inert organic solvent suchas dioxane, or N,N-dimethylformamide, at a temperature between 100° C.and 150° C. for 1 to 3 hours under microwave irradiation. Alternatively,the reactions can be carried out at a heated temperature such as atemperature between 100° C. and 140° C. for a longer reaction timewithout the use of microwave irradiation.

R. General Synthetic Route for Formula Idx (Scheme 69)

Compounds of interest Idx can be prepared according to Scheme 69.Starting with hydroxybenzonitriles XXIX, alkylation with methylbromoacetate gives esters XXX. Intramolecular cyclization of compoundsXXX gives benzooxazepin-3-ones IVr, which are in turn converted tobenzooxazepines IVs by reduction. Coupling of IVs with 2,4-dihalogenquinolines IIIa furnishes IIec. Subsequent coupling of IIec with variousamines XI affords compounds of interest Idx.

Esters XXX can be prepared from alkylation of hydroxybenzonitriles XXIXwith methyl bromoacetate. The reaction is typically carried out inacetone with potassium carbonate at room temperature for several hours.

Benzooxazepin-3-ones IVr can be prepared from esters XXX byintramolecular cyclization. The reaction can be carried out in methanolwith Raney nickel at room temperature for several hours under anatmospheric pressure of hydrogen.

Benzooxazepines IVs can be prepared from benzooxazepin-3-ones IVr byreduction of lactam. The reaction is typically conducted in an inertsolvent such as tetrahydrofuran, diethyl ether or mixtures thereof withlithium aluminium hydride, typically at 0° C., followed by stirring atreflux temperature for several hours.

Substituted quinolines IIec can be prepared from coupling ofbenzooxazepines IVs with 2,4-dihalogen quinolines IIIa. The reaction canbe carried out with a suitable base such as potassium carbonate, cesiumcarbonate, diisopropylethylamine, triethylamine, or1,8-diazabicyclo[5.4.0]undec-7-ene in an inert organic solvent such astoluene, tetrahydrofuran, 1-methyl-pyrrolidin-2-one orN,N-dimethylformamide, typically at a temperature between 100° C. and180° C. for 1 to 3 hours under microwave irradiation.

Compounds of interest Idx can be prepared by coupling of substitutedquinolines IIec with various amines XI. The reaction can be achieved bymicrowave irradiation at a temperature between 140° C. and 180° C. for 1to 3 hours with or without organic solvent such asN,N-dimethylformamide, 1-methyl-pyrrolidin-2-one or n-butyl alcohol.

General Synthetic Route for Formula Idy (Scheme 70)

Compounds of interest of formula Idy can be prepared according to Scheme70. Coupling of 2,4-dichloro-quinozalines IIIb with various amines XXXIfollowed by reaction with6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene 5,5-dioxides IVdaffords 2,4-disubstituted quinozalines IIef. Deprotection oftert-butyloxycarbonyl of IIef generates the target compounds Idy.

2-Chloro-4-amino quinozalines IIed can be prepared by coupling of IIIbwith various amines XXXI. The reaction can be carried out in thepresence of a suitable base such as triethylamine in a suitable solventsuch as methanol, tetrahydrofuran, dichloromethane or mixture thereof ata temperature between 0° C. to room temperature for several hours.

4-Disubstituted quinozalines IIef can be obtained by the coupling ofIIed with 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene 5,5-dioxidesIVd. The reaction can be carried out with or without an acid such as4-methylbenzenesulfonic acid and ammonium chloride, in a suitablesolvent such as ethanol or N,N-dimethylformamide at an elevatedtemperature between 50° C. and 120° C. for several hours, typically at70° C. overnight.

Compounds of interest of formula Idy can be prepared from deprotectionof tert-butyloxycarbonyl of 4 disubstituted quinozalines IIef. Thereaction can be carried out with a suitable acid such as trifluoroaceticacid or hydrochloric acid in a suitable solvent such as dichloromethane,ethyl acetate or 1,4-dioxane, at 0° C. to room temperature for 30minutes to 16 hours.

The invention also relates to a compound of formula (I) for use astherapeutically active substance.

The invention relates to a compound of formula (I) for use as amedicament.

The invention also relates to a pharmaceutical composition comprising acompound of formula (I) and a therapeutically inert carrier.

The invention relates in particular to the use of a compound of formula(I) for the preparation of a medicament for the treatment or prophylaxisof respiratory syncytial virus infection.

Said medicaments, e.g. in the form of pharmaceutical preparations, canbe administered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatine capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of suppositories, or parenterally, e.g. in the form ofinjection solutions with an effective amount of a compound as definedabove.

The above-mentioned pharmaceutical composition can be obtained byprocessing the compounds according to this invention withpharmaceutically inert inorganic or organic carriers. For example,lactose, corn starch or derivatives thereof, talc, stearic acids or itssalts and the like can be used, as such carriers for tablets, coatedtablets, dragées and hard gelatine capsules. Suitable carriers for softgelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Depending on the nature ofthe active substance no carriers are, however, usually required in thecase of soft gelatine capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, glycerol,vegetable oil and the like. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

The pharmaceutical composition can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The dosage depends on various factors such as manner of administration,species, age and/or individual state of health. The doses to beadministered daily are about 5-400 mg/kg, preferably about 10-100 mg/kg,and can be taken singly or distributed over several administrations.

A compound of formula (I) when manufactured according to the aboveprocess is also an object of the invention.

This invention relates to the use of a compound of formula (I) for themanufacture of a medicament for treatment or prophylaxis of RSVinfection.

The invention further relates to a method for the treatment orprophylaxis of respiratory syncytial virus infection, which methodcomprises administering an effective amount of a compound of formula(I).

The invention is illustrated by the following examples which have nolimiting character. Unless explicitly otherwise stated, all reactions,reaction conditions, abbreviations and symbols have the meanings wellknown to a person of ordinary skill in organic chemistry.

EXAMPLES

Intermediates and final compounds were purified by flash chromatographyusing one of the following instruments: i) Biotage SP1 system and theQuad 12/25 Cartridge module. ii) ISCO combi-flash chromatographyinstrument. Silica gel Brand and pore size: i) KP-SIL 60 Å, particlesize: 40-60 μM; ii) CAS registry NO: Silica Gel: 63231-67-4, particlesize: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang ChemicalCo., Ltd, pore: 200-300 or 300-400.

Intermediates and final compounds were purified by preparative HPLC onreversed phase column using X Bridge™ Perp C₁₈ (5 μm, OBD™ 30×100 mm)column or SunFire™ Perp C₁₈ (5 μm, OBD™ 30×100 mm) column.

LC/MS spectra were obtained using a MicroMass Plateform LC (Waters™alliance 2795-ZQ2000). Standard LC/MS conditions were as follows(running time 6 minutes):

Acidic condition: A: 0.1% formic acid in H₂O; B: 0.1% formic acid inacetonitrile;

-   Basic condition: A: 0.01% NH₃.H₂O in H₂O; B: acetonitrile;-   Neutral condition: A: H₂O; B: acetonitrile.

Mass spectra (MS): generally only ions which indicate the parent massare reported, and unless otherwise stated the mass ion quoted is thepositive mass ion (M+H)⁺.

The microwave assisted reactions were carried out in a Biotage InitiatorSixty.

NMR Spectra were obtained using Bruker Avance 400 MHz.

All reactions involving air-sensitive reagents were performed under anargon atmosphere. Reagents were used as received from commercialsuppliers without further purification unless otherwise noted.

Intermediate 1-1 2,4-Dichloro-8-methylquinoline

To a three necks round bottom flask equipped with a reflux condenser andthermometer containing phosphoryl chloride (400 mL) was added2-methylaniline (50 g, 0.47 mol) and propanedioic acid (73 g, 0.7 mol).The mixture was heated and stirred at 95° C. for 16 hours and then 145°C. for 1 hour. The volatiles were evaporated in vacuo and the residualblack oil was poured onto crashed ice with stirring. The resultingmixture was extracted with dichloromethane (300 mL×3). The combinedorganic layers were washed with a saturated aqueous solution of sodiumbicarbonate until the water phase was pH 7-8, then washed with brine(300 mL), dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash column chromatography (3% ethylacetate in petroleum ether) to afford 65 g of the pure product (yieldwas 65.3%). MS obsd. (ESI⁺) [(M+H)⁺] 212.

Intermediate 1-2 2,4-Dichloro-6-(methylsulfanyl)quinoline

1-(Methylsulfanyl)-4-nitrobenzene

To a suspension of p-nitrothiophenol (20 g, 0.129 mol) in water (150 mL)was added an aqueous solution of sodium hydroxide (75 mL, 2 N) at roomtemperature. After the mixture was stirred for 15 minutes and cooled to10° C., methyl iodide (57 g, 25 mL, 0.401 mol) was added slowly. Thereaction mixture was allowed to warm to room temperature and stirred for2.5 hours. The resulting mixture was extracted with diethyl ether (100mL×3). The organic layers were combined, washed with water (200 mL) andbrine (200 mL), dried over calcium sulfate and concentrated in vacuo.The residue was purified by silica gel column chromatography to afford11 g of 1-(methylsulfanyl)-4-nitrobenzene as a yellow solid.

4-(Methylsulfanyl)aniline

A suspension of 1-(methylsulfanyl)-4-nitrobenzene (10.5 g, 0.062 mol)and Raney nickel (5 g) in methanol (250 ml) was hydrogenated in a roundflask equipped with a balloon filled with hydrogen at room temperaturefor 16 hours. The resulting mixture was filtered and concentrated invacuo to afford 8.0 g of 4-(methylsulfanyl)aniline as colorless oil.

2,4-Dichloro-6-(methylsulfanyl)quinoline

Intermediate 1-2 can be prepared in analogy to Intermediate 1-1 by using4-(methylsulfanyl)aniline. MS obsd. (ESI⁺) [(M+H)⁺] 244.

Intermediate 1-3 6-Bromo-2,4-dichloroquinoline

Intermediate 1-3 can be prepared in analogy to Intermediate 1-1 by using4-bromoaniline. MS obsd. (ESI⁺) [(M+H)⁺] 276.

Intermediate 1-4 2,4-Dichloro-5-methylquinoline

Intermediate 1-4 can be prepared in analogy to intermediate 1-1 by using3-methylaniline. MS obsd. (ESI⁺) [(M+H)⁺] 212.

Intermediate 1-5 2,4-Dichloro-7-methylquinoline

Intermediate 1-5 can be prepared in analogy to intermediate 1-1 by using3-methylaniline. MS obsd. (ESI⁺) [(M+H)⁺] 212.

Intermediate 1-6 2,4-Dichloro-6-fluoro-quinoline

Intermediate 1-6 can be prepared in analogy to Intermediate 1-1 by using4-fluoroaniline. MS obsd. (ESI⁺) [(M+H)⁺] 216.

Intermediate 1-8 2,4-Dichloro-6-trideuteriomethyl-quinoline

Intermediate 1-8 can be prepared in analogy to Intermediate 1-1 by using4-trideuteriomethylaniline. MS obsd. (ESI⁺) [(M+H)⁺] 215.

Intermediate 1-9 Methyl 2,4-dichloro-quinoline-6-carboxylate

Intermediates 1-9 can be prepared in analogy to Intermediate 1-1 byusing methyl 4-aminobenzoate. MS obsd. (ESI⁺) [(M+H)⁺] 256.

Intermediate 1-10 2,4-Dichloro-7,8-difluoro-6-methylquinoline

Intermediate 1-10 can be prepared in analogy to Intermediate 1-1 byusing 2,3-difluoro-4-methylaniline. MS obsd. (ESI⁺) [(M+H)⁺] 248.

Intermediate 1-11 2,4-Dichloro-6-(trifluoromethoxy)quinoline

Intermediate 1-11 can be prepared in analogy to Intermediate 1-1 byusing 4-(trifluoromethoxy)aniline. MS obsd. (ESI⁺) [(M+H)⁺] 282.

Intermediate 1-12 2,4-Dichloro-6-(difluoromethoxy)quinoline

Intermediate 1-12 can be prepared in analogy to Intermediate 1-1 byusing 4-(difluoromethoxy)aniline. MS obsd. (ESI⁺) [(M+H)⁺] 264.

Intermediate 1-13 2,4-Dichloro-5-fluoro-6-methylquinoline

Intermediate 1-13 can be prepared in analogy to Intermediate 1-1 byusing 3-fluoro-4-methylaniline. MS obsd. (ESI⁺) [(M+H)⁺] 230.

Intermediate 1-14 2,4-Dichloro-7-fluoro-6-methylquinoline

Intermediate 1-14 can be prepared in analogy to Intermediate 1-1 byusing 3-fluoro-4-methylaniline. MS obsd. (ESI⁺) [(M+H)⁺] 230.

Intermediate 1-15 2,4-Dibromo-6-methylquinoline

Intermediate 1-15 can be prepared in analogy to Intermediate 1-1 byusing 4-methylaniline, propanedioic acid and phosphoryl bromide. MSobsd. (ESI⁺) [(M+H)⁺] 300, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.92 (s, 1 H),7.91-7.88 (d, J=0.8 Hz, 1 H), 7.80 (s, 1 H), 7.62-7.56 (dd, J=2.0, 8.4Hz, 1 H), 2.57 (s, 3 H).

Intermediate 1-16 2,4-Dichloro-1,6-naphthyridine

Methyl 4-aminopyridine-3-carboxylate

A mixture of compound 4-aminopyridine-3-carboxylic acid (100 g, 0.7 mol)and concentrated sulfuric acid (400 g, 4.0 mol) in absolute methanol(1.5 L) was stirred under reflux for 24 hours. The reaction mixture wasconcentrated in vacuo. The residue was diluted with ice-water (800 mL),basified with 2 N of aqueous solution of sodium hydroxide to about pH 10and then extracted with ethyl acetate (300 mL×3). The combined organiclayers were washed with water (500 mL), dried over sodium sulfate andconcentrated in vacuo to afford the crude product, which was used fornext step without further purification.

Methyl 4-(acetylamino)pyridine-3-carboxylate

A mixture of methyl 4-aminopyridine-3-carboxylate (100 g, 0.6 mol) andacetic anhydride (240 g, 2.4 mol) in anhydrous 1,4-dioxane (1.2 L) wasstirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo and diluted with water (800 mL). The mixture wasneutralized with a saturated aqueous solution of sodium bicarbonate topH 7. The formed solid was collected by filtration and dried in vacuo toafford 50 g of methyl 4-(acetylamino)pyridine-3-carboxylate as a whitesolid.

1-Benzyl-4-hydroxy-1,6-naphthyridin-2(1H)-one

A mixture of methyl 4-(acetylamino)pyridine-3-carboxylate (70 g, 0.36mol) and sodium hydride (50 g, 1.25 mol, 60% in mineral oil) inanhydrous tetrahydrofuran (800 mL) was stirred at room temperature for30 minutes. To the above mixture was added bromomethylbenzene (60 g,0.36 mmol) and the resulting mixture was stirred at room temperatureovernight. The reaction mixture was poured onto crashed ice (600 mL),concentrated in vacuo, and washed with ethyl acetate (400 mL). Theaqueous layer was neutralized by addition of 3 N aqueous solution ofhydrochloric acid to pH 7. The formed solid was collected by filtrationand dried in vacuo to afford 24 g of1-benzyl-4-hydroxy-1,6-naphthyridin-2(1H)-one as a pale yellow solid.

1,6-Naphthyridine-2,4(1H,3H)-dione

A mixture of 1-benzyl-4-hydroxy-1,6-naphthyridin-2(1H)-one (21 g, 0.08mol) and trifluoromethanesulfonic acid (100 mL) was heated with stirringat 120° C. overnight. The reaction mixture was used for the next stepdirectly.

2,4-Dichloro-1,6-naphthyridine

A mixture of 1,6-naphthyridine-2,4(1H,3H)-dione (10 g, 0.06 mol) andphosphoryl chloride (180 g) was heated with stirring at 100° C. for 3hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was poured into ice-water (200 g) andextracted with ethyl acetate (200 mL×5). The combined organic layerswere dried over sodium sulfate, concentrated in vacuo to afford thecrude product. ¹H NMR (400 MHz, CD₃OD) δ ppm 9.57 (s, 1 H), 8.90-8.89(d, J=5.6 Hz, 1 H), 8.12 (s, 1 H), 7.94-7.93 (d, J=6.0 Hz, 1 H).

Intermediate 1-17 2,4-Dichloro-6-difluoromethylquinoline

4-Aminobenzaldehyde

To a solution of 4-nitrobenzaldehyde (2.0 g, 0.133 mol) in acetic acid(150 mL) and water (15 mL) was added iron powder (1.48 g, 0.265 mol).The reaction was stirred overnight at room temperature. The mixture wasfiltered and extracted with dichloromethane (50 mL×3). Then the organiclayer was dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash column chromatography (eluting with10% ethyl acetate in petroleum ether) to afford 1.2 g of the pureproduct (yield was 75%).

2,4-Dichloroquinoline-6-carbaldehyde

A mixture of 4-aminobenzaldehyde (14 g, 0.116 mol), propanedioic acid(14.4 g, 0.139 mol) and phosphoryl chloride (180 g) was heated withstirring at 95° C. for 16 hours. The reaction mixture was cooled to roomtemperature and concentrated in vacuo. The residue was purified by flashcolumn chromatography afford 150 mg of the pure product (yield was0.57%).

2,4-Dichloro-6-difluoromethylquinoline

A mixture of 2,4-dichloroquinoline-6-carbaldehyde (45.2 mg, 0.2 mmol)and diethylaminosulfur trifluoride (32.2 mg, 0.2 mmol) in1,2-dichloroethane (15 mL) was refluxed overnight. The reaction mixturewas cooled to room temperature and concentrated in vacuo. The residuewas purified by thin layer chromatography to afford 20 mg of the desiredproduct (yield was 40.3%), MS obsd. (ESI⁺) [(M+H)⁺] 248, ¹H NMR (400MHz, CDCl₃) δ ppm 8.28 (s, 1 H), 8.10-8.05 (d, J=8.8 Hz, 1 H), 7.90-7.82(d, J=8.4 Hz, 1 H), 7.53 (s, 1 H), 6.95-6.62 (t, J=56 Hz, 1 H).

Intermediate 2-1 2,3,4,5-Tetrahydro-1,4-benzothiazepine

Methyl 2-sulfanylbenzoate

To a cooled solution of concentrated sulfuric acid (72 g) in methanol(1.5 L) at 0° C., was added 2-sulfanylbenzoic acid (300 g, 1.95 mol) inportions under argon atmosphere. After being refluxed with stirring for18 hours, the reaction mixture was concentrated in vacuo. The residuewas diluted with water (800 mL), basified with a saturated aqueoussolution of sodium bicarbonate to about pH 7, and extracted withdichloromethane (600 mL×3). The combined organic layers were washed withbrine (800 mL), dried over sodium sulfate, filtered and concentrated invacuo to afford 300 g of methyl 2-sulfanylbenzoate (yield was 91%) as alight yellow oil, which was used for the next step without furtherpurification.

3,4-Dihydro-1,4-benzothiazepin-5(2H)-one

To a cooled solution of methyl 2-sulfanylbenzoate (200 g, 1.19 mol) intetrahydrofuran and N,N-dimethylformamide (2 L, V/V=1/1) was added2-chloroethanamine hydrochloride (138 g, 1.19 mol) at 0° C. followed bysodium hydride (143 g, 3.57 mol, 60% in mineral oil) in portions. Afterbeing stirred at room temperature overnight, the reaction mixture waspoured into ice-water and extracted with ethyl acetate (900 mL×4). Theorganic layers were combined, washed with brine (900 mL×3), dried oversodium sulfate and concentrated in vacuo. The residue was stirred in amixture solution of ethyl acetate and petroleum ether (300 mL, V/V=1/1)for 1 hour. The solid was collected by filtration and dried in vacuo toafford 100 g of 3,4-dihydro-1,4-benzothiazepin-5(2H)-one (yield was47%).

2,3,4,5-Tetrahydro-1,4-benzothiazepine

To a bottle containing a cooled suspension of lithium aluminum hydride(44 g, 1.17 mol) in dry tetrahydrofuran (1.5 L) was added3,4-dihydro-1,4-benzothiazepin-5(2H)-one (150 g, 0.84 mol) in portionsat 0° C. After being refluxed for 18 hours, the reaction mixture wascooled to 0° C., followed by addition of water (25 mL) dropwise. Thereaction mixture was then filtered through a pad of celite and washedwith dichloromethane. The filtrate was dried over sodium sulfate andevaporated in vacuo to afford 125 g of2,3,4,5-tetrahydro-1,4-benzothiazepine (yield was 90%), which was usedfor the next step without further purification.

Intermediate 2-2 and 2-38-Methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (Intermediate 2-2) and8-Fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine (Intermediate 2-3)

4-Fluoro-2-sulfanylbenzoic acid

To a cooled solution of 2-amino-4-fluoro-benzoic acid (0.93 g, 6 mmol)in water (3 mL) was added concentrated hydrochloric acid (1.2 mL), thena cold solution of sodium nitrite (0.41 g, 6 mmol) in water (2 mL) wasadded dropwise at 5° C. After the addition, the mixture was stirred for30 minutes at that temperature. A cooled solution of disodium disulphideprepared with boiled water (2 mL), sodium sulfide nonahydrate (1.57 g,6.66 mmol), sulfur (0.2 g, 6.6 mmol) and a solution of sodium hydroxide(0.6 mL, 10 mol/L) was added dropwise into the above mixture at 5° C.After being stirred for 2 hours at room temperature, the mixture wasacidified with hydrochloric acid. The formed precipitate was filtered,washed with water, and dried in vacuo to afford 1.4 g of the disulfidederivative as a yellow solid (yield was 70%). MS obsd. (ESI⁻) [(M−H)⁻]341.

A mixture of disulfide (1.4 g, 4.1 mmol) and zinc powder (0.18 g, 2.76mmol) in acetic acid (5 mL) was refluxed for 4 hours, and then cooled toroom temperature. The formed precipitate was collected by filtration,and then boiled in an aqueous solution of sodium hydroxide (0.15 g in1.2 mL of water) for 30 minutes. After being cooled to 0° C., themixture was acidified with hydrochloric acid. The formed solid wascollected by filtration, washed with water, and dried in vacuo to afford0.5 g of the product (yield was 36%). MS obsd. (ESI⁻) [(M−H)⁻] 171.

Methyl 4-fluoro-2-sulfanylbenzoate

A mixture of 4-fluoro-2-sulfanylbenzoic acid (6.0 g, 34.9 mmol),concentrated sulfuric acid (6 mL) in methanol (200 mL) was refluxed for18 hours under argon atmosphere. The resulting mixture was concentratedin vacuo. The residue was diluted with ethyl acetate, washed with water,basified with a saturated aqueous solution of sodium bicarbonate toabout pH 8. The organic layer was washed with brine, dried over sodiumsulfate, and concentrated in vacuo to afford 4.54 g of the crude productas a brown oil (yield was 70%), which was used directly for the nextstep without further purification. MS obsd. (ESI⁻) [(M−H)⁻] 185.

8-Methoxy-3,4-dihydro-1,4-benzothiazepin-5(2H)-one and8-Fluoro-3,4-dihydro-1,4-benzothiazepin-5(2H)-one

To a solution of methyl 4-fluoro-2-sulfanylbenzoate (3.0 g, 16 mmol) and2-chloroethanamine hydrochloride (1.88 g, 16 mmol) inN,N-dimethylformamide (30 mL), sodium hydride (1.94 g, 48 mmol, 60% inmineral oil) was added in portions. The reaction mixture was stirred at100° C. overnight. The solvent was removed under reduced pressure. Theresidue was diluted with water, then a mixture of ethyl acetate andpetroleum ether (1/10, V/V). The resulting mixture was stirred for 1hour. The resulting precipitate was collected by filtration, washed withdiethyl ether and petroleum ether, dried in vacuo to afford a mixture of8-methoxy-3,4-dihydro-1,4-benzothiazepin-5(2H)-one and8-fluoro-3,4-dihydro-1,4-benzothiazepin-5(2H)-one. The above mixture waspurified by flash column to afford 0.75 g of the product8-methoxy-3,4-dihydro-1,4-benzothiazepin-5(2H)-one as a pale white solid(yield was 22%), MS obsd. (ESI⁺) [(M+H)⁺] 210, and 0.75 g of the product8-fluoro-3,4-dihydro-1,4-benzothiazepin-5(2H)-one as a pale white solid(yield was 23%), MS obsd. (ESI⁺) [(M+H)⁺] 198.

Intermediate 2-2 8-Methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine

Intermediate 2-2 can be prepared in analogy to intermediate 2-1 by using8-methoxy-3,4-dihydro-1,4-benzothiazepin-5(2H)-one (yield was 90%). MSobsd. (ESI⁺) [(M+H)⁺] 196.

Intermediate 2-3 8-Fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine

Intermediate 2-3 can be prepared in analogy to intermediate 2-1 by using8-fluoro-3,4-dihydro-1,4-benzothiazepin-5(2H)-one (yield was 96%). MSobsd. (ESI⁺) [(M+H)⁺] 184.

Intermediate 2-4 7-Fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine

Intermediate 2-4 can be prepared in analogy to intermediate 2-1 by using5-fluoro-2-sulfanylbenzoic acid. MS obsd. (ESI⁺) [(M+H)⁺] 184.

Intermediate 2-5 9-Fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine

Intermediate 2-5 can be prepared in analogy to intermediate 2-1 by using3-fluoro-2-sulfanylbenzoic acid. MS obsd. (ESI⁺) [(M+H)⁺] 184.

Intermediate 2-6 8-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine

Methyl 2-hydroxy-4-methylbenzoate

A mixture of 2-hydroxy-4-methylbenzoic acid (100.0 g, 657.2 mmol),concentrated sulfuric acid (50 mL) in methanol (1000 mL) was refluxedfor 20 hours under nitrogen atmosphere. The resulting mixture wasconcentrated in vacuo. The residue was poured into ice-water, extractedwith ethyl acetate (1000 mL). The organic layer was washed withsaturated sodium bicarbonate, brine, dried over sodium sulfate,concentrated in vacuo to afford 109 g of the crude product of methyl2-hydroxy-4-methylbenzoate as light brown oil, which was used directlyin the next step without further purification.

Methyl 2-[(dimethylcarbamothioyl)oxy]-4-methylbenzoate

To a solution of methyl 2-hydroxy-4-methylbenzoate (109 g, 657.2 mmol)and 1,4-diazabicyclo[2.2.2]octane (147.4 g, 1314.4 mmol) inN,N-dimethylformamide (300 mL) was added a solution ofN,N-dimethylcarbamothioyl chloride (97.5 g, 788.6 mmol) inN,N-dimethylformamide (100 mL) at room temperature. After being heatedat 60° C. for 4 hours, the mixture was cooled and poured onto ice. Theformed precipitate was collected by filtration, washed with water (300mL×3) and dried in vacuo to afford 137 g of methyl2-[(dimethylcarbamothioyl)oxy]-4-methylbenzoate as an off-white solid(yield was 82%).

Methyl 2-[(dimethylcarbamoyl)sulfanyl]-4-methylbenzoate

Methyl 2-[(dimethylcarbamothioyl)oxy]-4-methylbenzoate (52.0 g, 205.5mmol) in a round bottle flask which was vacuumed and backfilled withnitrogen, was heated at 210° C. for 4 hours. The mixture was then cooledto room temperature and used for next step without further purification.

4-Methyl-2-sulfanylbenzoic acid

A round bottle flask containing a mixture of methyl2-[(dimethylcarbamoyl)sulfanyl]-4-methylbenzoate (50 g, 197.6 mmol) andan aqueous solution of sodium hydroxide (120 mL, 4 N) was vacuumed andbackfilled with nitrogen 3 times. After being refluxed for 2 hours, theresulting mixture was cooled to 0° C. and acidified with an aqueoussolution of hydrochloric acid (45 mL, 6 N). The formed precipitate wascollected by filtration, and then dissolved in ethyl acetate (500 mL).The solution was dried over anhydrous sodium sulfate, and concentratedin vacuo to afford 4-methyl-2-sulfanylbenzoic acid as a light yellowsolid.

8-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine

Intermediate 2-6 can be prepared in analogy to intermediate 2-1 by using4-methyl-2-sulfanylbenzoic acid. MS obsd. (ESI⁺) [(M+H)⁺] 180.

Intermediate 2-7 8-Chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine

4-Chloro-2-sulfanylbenzoic acid

To a cooled mixture of concentrated hydrochloric acid (6 mL) and ice (10g) was added slowly a solution of 2-amino-4-chlorobenzoic acid (4 g,23.3 mmol), sodium hydroxide (0.94 g, 23.5 mmol) and sodium nitrite (1.6g, 23.3 mmol) in water (30 mL) in an ice bath. The resulting mixture wasstirred at 0° C. for 1 hour. A solution of potassiumethoxymethanedithioate (20.8 g, 65.2 mmol) in water (40 mL) in a beakerwas heated to 65° C. The cold diazonium salt solution was added slowlyto the above hot solution while evolution of gas was observed. After theaddition the mixture was cooled to room temperature and acidified toabout pH 3 with an aqueous solution of hydrochloric acid (4 N). Theaqueous phase was decanted from the resulting semisolid and the sludgewas dissolved in 10% aqueous sodium hydroxide (20 mL). The solution washeated for 2 hours at 100° C. followed by addition of sodiumhydrosulfite (2 g). The resulting mixture was heated with stirring at100° C. for an additional 10 minutes, then cooled to room temperatureand filtered through a pad of celite. The filtrate was acidified toabout pH 4 with concentrated hydrochloric acid. The formed solid wascollected by filtration, washed with water, and dissolved in methanol(10 mL) and diethyl ether (150 mL). The solution was dried over sodiumsulfate and concentrated in vacuo to afford 2.8 g of4-chloro-2-sulfanylbenzoic acid as a yellow solid (yield was 63%).

8-Chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine

Intermediate 2-7 can be prepared in analogy to intermediate 2-1 by using4-chloro-2-sulfanylbenzoic acid. MS obsd. (ESI [(M+H)⁺] 200.

Intermediate 3 5-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine

1-(2-Sulfanylphenyl)ethanone

To a stirred suspension of aluminium chloride (10.50 g, 78.8 mmol) indry benzene (200 mL) was added a solution of1-[2-(benzylsulfanyl)phenyl]ethan-1-one (11.93 g, 49.2 mmol) in drybenzene (100 mL) dropwise in an ice bath under argon atmosphere. Afterthe reaction mixture being stirred at room temperature overnight, thereaction was quenched by the cautious addition of ice-water. Theseparated organic layer was washed with water and extracted with 5%aqueous solution of sodium hydroxide (300 mL). The aqueous layer wasacidified to about pH 3 with concentrated hydrochloric acid (12 N) andextracted with dichloromethane (300 mL×3). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate,concentrated in vacuo to afford 6.47 g of the crude product1-(2-sulfanylphenyl)ethanone.

5-Methyl-2,3-dihydro-1,4-benzothiazepine

To a solution of 1-(2-sulfanylphenyl)ethanone (6.40 g, 42.05 mmol) inethanol (80 mL) was added an aqueous solution of potassium hydroxide(7.08 g, 126.14 mmol in 30 mL of water) and an aqueous solution of2-bromoethanamine hydrobromide (9.48 g, 46.25 mmol in 30 mL of water).After being stirred at room temperature for 6 hours, the reactionmixture was concentrated in vacuo to remove most of ethanol andextracted with dichloromethane (60 mL×3). The combined organic layerswere washed with brine (100 mL), dried over anhydrous sodium sulfate,and concentrated in vacuo. The residue was purified by flash columnchromatography to give 5.92 g of5-methyl-2,3-dihydro-1,4-benzothiazepine.

5-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine

To a solution of 5-methyl-2,3-dihydro-1,4-benzothiazepine (5.92 g, 33.40mmol) in methanol (100 mL) was added a solution of sodium borohydride(3.16 g, 83.49 mmol) in water (60 mL). After being stirred at roomtemperature overnight, the reaction mixture was acidified withconcentrated hydrochloric acid, and then stirred at room temperature for30 minutes. After being adjusted to pH 9 with an aqueous solution ofsodium hydroxide, the resulting mixture was extracted with ethyl acetate(60 mL×3). The combined organic layers were washed by brine (100 mL),dried over anhydrous sodium sulfate, and concentrated in vacuo to afford5.6 g of 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, MS obsd.(ESI⁺) [(M+H)⁺] 180.

Intermediate 41-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone

1-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone

To a solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (5 g, 30.3 mmol)in dry dichloromethane (100 mL) was added triethylamine (5.06 mL, 36.3mmol) at room temperature, followed by the dropwise addition of aceticanhydride (3.43 mL, 36.3 mmol) at 0° C. under nitrogen. The resultingsolution was stirred for 1 hour whilst allowing the temperature to riseslowly to room temperature. The mixture was washed with brine (50 mL×2),dried over sodium sulfate, filtered and concentrated in vacuo to afford6.28 g of product as yellow oil, which was used for next step withoutfurther purification.

1-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone

To a cooled solution of1-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (6.27 g, 30.2 mmol)in dichloromethane (100 mL) was added a suspension of3-chloroperoxybenzoic acid (20.9 g, 90.8 mmol, 75% purity) indichloromethane (50 mL) at 10° C. After the addition, the resultingmixture was stirred for 1 hour whilst allowing the temperature to riseslowly to room temperature. The mixture was washed with a saturatedaqueous solution of sodium carbonate (100 mL×2), a saturated aqueoussolution of sodium sulfite (100 mL×2) and brine (100 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated in vacuo.The residue was stirred in diethyl ether (50 mL) and the solid wascollected by filtration and dried in vacuo to afford 6 g of1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone as awhite powder.

Intermediate 5 2,3,4,5-Tetrahydro-1,4-benzothiazepine 1,1-dioxide

To a solution of1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (240 g,1.0 mol) in ethanol (1.0 L) was added sodium hydroxide (200 g, 5.0 mol)and water (700 mL). The mixture was refluxed overnight and thenconcentrated in vacuo. The residue was extracted by ethyl acetate (1500mL×4). The combined organic layers were extracted by hydrochloric acid(2000 mL, 3 N). The acidic aqueous layer was washed with ethyl acetate(1500 mL×2), then basified with a saturated aqueous solution of sodiumbicarbonate to pH >7, and extracted with ethyl acetate (1500 mL×4). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo to afford 151 g of2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (yield was 76%), MSobsd. (ESI⁺) [(M+H)¹] 198, ¹H NMR (400 MHz, DMSO-d⁶) δ ppm 7.89 (dd,J=1.2, 7.6 Hz, 1 H), 7.56 (t, J=7.6 Hz, 1 H), 7.47 (t, J=7.6 Hz, 1 H),7.42 (d, J=7.6 Hz, 1 H), 4.04 (s, 2 H), 3.32-3.30 (m, 2 H), 3.30-3.25(m, 2 H), 2.64 (s, 1 H).

Intermediate 6 2,3,4,5-Tetrahydro-1,4-benzothiazepine 1-oxide

1-(1-Oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone

To a cooled solution of1-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (70 g, 0.33 mol) indichloromethane (700 mL) was added a solution of 3-chloroperoxybenzoicacid (67 g, 0.33 mol) in dichloromethane (800 mL) dropwise at 0° C.After the addition, the reaction was stirred at the same temperature for15 minutes. The resulting reaction mixture was washed with a saturatedaqueous solution of sodium carbonate (500 mL×2) and a saturated aqueoussolution of sodium sulfite (500 mL×2). The combined aqueous layers wereextracted with dichloromethane (200 mL×2), dried over sodium sulfate andconcentrated in vacuo. The residue was purified by flash chromatography(eluting with 1-2% methanol in dichloromethane) to afford 57 g of thedesired product (yield was 77%).

2,3,4,5-Tetrahydro-1,4-benzothiazepine 1-oxide

Intermediate 6 was prepared in analogy to intermediate 5 by using1-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (yield was66%), MS obsd. (ESI⁺) [(M+H)⁺] 181, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.72(dd, J=1.6, 7.6 Hz, 1 H), 7.52-7.48 (m, 2 H), 7.33 (dd, J=1.6, 7.2 Hz, 1H), 4.21-4.11 (m, 1 H), 3.82-3.80 (m, 1 H), 3.62-3.50 (m, 2 H),3.22-3.19 (m, 2 H).

Intermediate 7 (5Z)—N-Methoxy-1,2,3,4-tetrahydro-5H-2-benzazepin-5-imine

A mixture of 1,2,3,4-tetrahydro-1-benzazepin-5-one (500 mg, 2.530 mmol),O-methyl hydroxylamine hydrochloride (211 mg, 2.530 mmol), sodiumacetate (208 mg, 2.530 mmol) and sodium carbonate (536 mg, 5.060 mmol)in ethanol was refluxed for 3 hours. The resulting mixture wasconcentrated in vacuo to remove ethanol and to the residue was addedwater (15 mL). The residue in water was extracted with dichloromethane(15 mL×3). The organic layers were combined, dried over sodium sulfate,and concentrated in vacuo to afford 326 mg of the desired product (yieldwas 67%).

Intermediate 8 5,5-Difluoro-2,3,4,5-tetrahydro-1H-benzazepine

1-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2,2,2-trifluoroethanone

To a cooled solution of 1,2,3,4-tetrahydro-1-benzazepin-5-onehydrochloride (33.7 g, 0.17 mol) in dichloromethane (500 mL) at 0° C.,was added triethylamine (52 g, 0.51 mol) dropwise followed bytrifluoroacetic anhydride (36 g, 0.17 mmol). After being stirred at roomtemperature for 3 hours, the resulting mixture was diluted with water(300 mL). The aqueous layer was extracted with dichloromethane (500 mL).The combined organic layers were washed with a saturated aqueoussolution of sodium bicarbonate (500 mL) and brine (500 mL), dried oversodium sulfate and concentrated in vacuo. The residue was purified byflash chromatography (eluting with 16% ethyl acetate in petroleum ether)to afford 40 g of the desired product (yield was 89%).

1-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2,2,2-trifluoroethanone

A solution of2-(trifluoroacetyl)-1,2,3,4-tetrahydro-5H-2-benzazepin-5-one (40 g,0.156 mol) in N,N-diethylaminosuflur trifluoride (104 g, 0.468 mol) washeated at 70° C. for 3 hours. The reaction mixture was poured intoice-water (600 mL) and extracted with dichloromethane (800 mL). Theorganic layer was washed with a saturated aqueous solution of sodiumbicarbonate (500 mL) and brine (500 mL), dried over sodium sulfate, andconcentrated in vacuo. The residue was purified by flash chromatography(eluting with 16% ethyl acetate in petroleum ether) to give 33 g of thedesired product (yield was 76%).

5,5-Difluoro-2,3,4,5-tetrahydro-1H-benzazepine

To a cooled solution of1-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2,2,2-trifluoroethanone(33 g, 0.184 mmol) in methanol was added an ammonia methanol solution(300 mL, 7 M) at 0° C. After being stirred at 0° C. for 2 hours, thereaction mixture was concentrated in vacuo. The residue was purified byflash chromatography (eluting with 1025% ethyl acetate in petroleumether) to afford 18 g of the desired product as a purple oil (yield was83.3%), MS obsd. (ESI⁺) [(M+H)⁺] 184, ¹H NMR (400 MHz, CDCl₃) δ ppm7.64-7.60 (m, 1 H), 7.34-7.25 (m, 2 H), 7.16-7.14 (m, 1 H), 7.01 (s, 2H), 3.33-3.30 (m, 2 H), 2.33-2.24 (m, 2 H).

Intermediate 9-1 3-(Aminomethyl)-N,N-dibenzyltetrahydrofuran-3-amine

3-(Dibenzylamino)tetrahydrofuran-3-carbonitrile

To a cooled solution of dibenzylamine (31.9 g, 162 mmol) in acetic acid(100 mL) at 0° C., dihydrofuran-3(2H)-one (7.0 g, 81 mmol) was addedfollowed by trimethylsilyl-formonitrile (14.4 g, 145.8 mmol). Afterbeing stirred at room temperature for 16 hours, the reaction mixture waspoured into water (100 mL), adjusted to pH 7 with sodium bicarbonate,exacted with ethyl acetate (100 mL×2). The combined organic layers werewashed with brine (150 mL), dried over sodium sulfate and concentratedin vacuo. The residue was purified by column chromatography to afford2.2 g of the desired product (yield was 9.28%).

3-(Aminomethyl)-N,N-dibenzyltetrahydrofuran-3-amine

To a cooled solution of 3-(dibenzylamino)tetrahydrofuran-3-carbonitrile(2.2 g, 7.5 mmol) in tetrahydrofuran (50 mL) at 0° C., was added lithiumaluminium hydride (855 mg, 22.5 mmol). After the mixture being stirredfor 16 hours at room temperature, the reaction was quenched by additionof water (5 mL). The resulting mixture was filtered and the filtrate wasconcentrated in vacuo to afford 1.3 g of the crude product (yield was58%).

Intermediate 9-2 3-(Aminomethyl)-N,N-dibenzyloxetan-3-amine

Intermediate 9-2 can be prepared in analogy to intermediate 9-1 by usingoxetan-3-one. MS obsd. (ESI⁺) [(M+H)⁺] 283.

Intermediate 9-3 1-(Aminomethyl)-N,N-dibenzylcyclobutanamine

Intermediate 9-3 can be prepared in analogy to intermediate 9-1 by usingcyclobutanone. MS obsd. (ESI⁺) [(M+H)⁺] 281.

Intermediate 9-4 3-(Aminomethyl)-N,N-dibenzylthietan-3-amine

3,3-Dimethoxythietane

To a solution of 1,3-dibromo-2,2-dimethoxy-propane (102 g, 389 mmol) inN,N-dimethylformamide (1200 mL) was added sodium sulfide (66.8 g, 506mmol), the mixture was refluxed for 3 days. The mixture was cooled toroom temperature, diluted with diethyl ether (1200 mL), washed withwater (1200 mL) and brine (1200 mL), dried over sodium sulphate andconcentrated in vacuo to afford 40 g of the product as a yellowish oil(yield was 77%).

Thietan-3-one

To a solution of 3,3-dimethoxythietane (40 g, 600 mmol) indichloromethane (2500 mL) was added dioxosilane (160 g). The mixture wasrefluxed for 2 days. The mixture was cooled to room temperature andfiltered through a pad of celite. The filtrate was concentrated in vacuoto afford the desired product.

3-(Aminomethyl)-N,N-dibenzylthietan-3-amine

Intermediate 9-4 can be prepared in analogy to intermediate 9-1 by usingthietan-3-one. MS obsd. (ESI⁺) [(M+H)⁺] 299, ¹H NMR (400 MHz, CD₃OD) δppm 7.21-7.14 (m, 8 H), 7.11-7.08 (m, 2 H), 3.74 (s, 4 H), 3.48-3.45 (m,2 H), 3.26 (s, 2 H), 2.66-2.64 (m, 2 H), 1.49 (s, 2 H).

Intermediate 9-5 1-(Aminomethyl)-N,N-dibenzylcyclohexanamine

Intermediate 9-5 can be prepared in analogy to intermediate 9-1 by usingcyclohexanone. MS obsd. (ESI⁺) [(M+H)⁺] 309.

Intermediate 9-6 (4-Aminomethyl-tetrahydropyran-4-yl)-dibenzyl-amine

Intermediate 9-6 can be prepared in analogy to intermediate 9-1 by usingtetrahydropyran-4-one. MS obsd. (ESI⁺) [(M+H)⁺] 311.

Intermediate 10 N-[(3-Aminooxetan-3-yl)methyl]-2,2,2-trifluoroacetamide

N-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-2,2,2-trifluoroacetamide

To a solution of 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine (3.0 g, 10.6mmol) in dichloromethane (30 mL) in an ice bath was added dropwisetrifluoroacetic anhydride (2.5 g, 11.7 mmol). After the mixture beingstirred at room temperature overnight, the reaction was quenched byaddition of a saturated aqueous solution of sodium bicarbonate at 0° C.The resulting mixture was extracted with dichloromethane, dried oversodium sulfate and concentrated in vacuo to afford 4.0 g of the crudeproduct as yellow oil.

N-[(3-Aminooxetan-3-yl)methyl]-2,2,2-trifluoroacetamide

To a solution ofN-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2,2,2-trifluoroacetamide (4.0g, 10.57 mmol) in methanol (80 mL) was added 20% palladium hydroxide oncarbon (0.8 g) and trifluoroacetic acid (one drop). The mixture wasstirred at room temperature under hydrogen overnight and then filtered.The filtrate was concentrated in vacuo to afford the crude product as awhite solid.

Intermediate 11 tert-Butyl [(3-aminooxetan-3-yl)methyl]carbamate

tert-Butyl {[3-(dibenzylamino)oxetan-3-yl]methyl}carbamate

To a solution of 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine (10.0 g,35.41 mmol) in tetrahydrofuran (100 mL) was added an aqueous solution ofsodium bicarbonate (8.6 g, 102.4 mmol dissolved in 50 mL of water) and asolution of di-tert-butyl dicarbonate (8.9 g, 51.08 mmol) intetrahydrofuran (30 mL). The mixture was stirred at room temperatureovernight, concentrated in vacuo to remove most of the organic solvent,and the aqueous residue was extracted with dichloromethane (100 mL×3).The organic layers were combined, washed with brine (150 mL), dried oversodium sulfate and concentrated in vacuo to afford 13.0 g of the crudeproduct, which was used for the next step without any purification.

tert-Butyl [(3-aminooxetan-3-yl)methyl]carbamate

A mixture of tert-butyl {[3-(dibenzylamino)oxetan-3-yl]methyl}carbamate(13.0 g, crude), 20% palladium hydroxide on carbon (2.0 g) andtrifluoroacetic acid (0.5 mL) in methanol (20 mL) was stirred overnightunder hydrogen atmosphere (1 bar). After being basified with ammoniasolution in methanol, the resulting mixture was filtered andconcentrated in vacuo to afford 5.8 g of the crude product, which wasused for the next step without any purification.

Intermediate 12 tert-Butyl [1-(2-aminoethyl)-cyclopropyl]carbamate

3-(Benzyloxy)propanenitrile

To a mixture of benzyl alcohol (108 g, 1 mol) and 40% aqueous solutionof sodium hydroxide (10 mL) was added prop-2-enenitrile (58.3 g, 1.1mol) and the mixture was stirred for 6 hours at room temperature. Themixture was neutralized with 1 N hydrochloric acid, and extracted withdichloromethane (300 mL). The organic layer was washed with 5% solutionof sodium hydroxide (300 mL) and brine (300 mL), dried over sodiumsulfate and concentrated in vacuo to afford 150 g of the desiredcompound (yield was 93%).

1-[2-(benzyloxy)ethyl]cyclopropanamine

To a solution of 3-(benzyloxy)propanenitrile (16.9 g 105 mmol) indiethyl ether (400 mL) were added titanium isopropoxide (35.7 mL, 115mmol) and ethyl magnesium bromide (210 mL, 1 M in diethyl ether)successively at room temperature. After being stirred for 0.5 hour,boron trifluoride etherate (27 mL, 525 mmol) was added. After stirringfor another 0.5 hour, 10% aqueous solution of sodium hydroxide (ca. 5.5mL) was introduced to the above mixture. The resulting mixture wasacidified with 1N hydrochloric acid to pH 3, and then washed withdichloromethane. The aqueous layer was basified with 5% aqueous solutionof sodium hydroxide to pH 8˜9 and extracted with dichloromethane (100mL). The organic layer was washed with brine (100 mL), dried over sodiumsulfate and concentrated in vacuo to afford 11 g of1-[2-(benzyloxy)ethyl]cyclopropanamine (yield was 55%).

2-(1-Aminocyclopropyl)ethanol hydrochloride

To a mixture of 1-[2-(benzyloxy)ethyl]cyclopropanamine (13.2 g, 69mmol), 10% palladium on carbon (3.0 g) and propan-2-ol (100 mL) wasadded a solution of hydrochloride in propan-2-ol (100 mL, 5-6 N). Themixture was shaken at 40° C. under hydrogen pressure of 4 atmospheresuntil hydrogen uptake ceased. The catalyst was removed by filtration andwashed with propan-2-ol. The filtrate was concentrated in vacuo toafford 8.8 g of the salt as a viscous oil (yield was 84.6%).

tert-Butyl [1-(2-hydroxyethyl)cyclopropyl]carbamate

To a solution of 2-(1-amino-cyclopropyl)-ethanol hydrochloride (1:1)(8.8 g, 64.4 mmol) in tetrahydrofuran (63 mL) was added water (1.5 mL),triethylamine (18.3 mL, 130 mmol) and a solution of di-tert-butyldicarbonate (15.46 g, 70.9 mmol) in tetrahydrofuran (21 mL). Theresulting mixture was stirred at room temperature for 16 hours. Themixture was concentrated in vacuo and the residue was dissolved indiethyl ether (100 mL). The organic solution was washed with an aqueoushydrochloric acid solution (0.1 N, 50 mL) and brine (50 mL), dried oversodium sulfate and concentrated in vacuo. The residue was triturated inwater and filtered to afford 9.3 g of the pure product as a white solid(yield was 71%).

2-{1-[(tert-Butoxycarbonyl)amino]-cyclopropyl}ethyl methanesulfonate

To a cooled solution of tert-butyl[1-(2-hydroxyethyl)cyclopropyl]carbamate (8.0 g, 0.04 mol) andtriethylamine (12.14 g) in anhydrous tetrahydrofuran (120 mL) at −20° C.was added a solution of mesyl chloride (17.8 g) in anhydroustetrahydrofuran (30 mL). The resulting mixture was allowed to warm toroom temperature and stirred at this temperature for 2 hours. Theresulting mixture was poured into ice-water (50 mL) and the separatedorganic layer was washed with brine (100 mL), dried over sodium sulfateand concentrated in vacuo. The residue was triturated with petroleumether and filtered to give 9.5 g of the pure product as an orange solid(yield was 95%).

tert-Butyl1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]cyclopropylcarbamate

To a solution of 2-{1-[(tert-butoxycarbonyl)amino]-cyclopropyl}ethylmethanesulfonate (9.5 g, 344.3 mmol) in anhydrous N,N-dimethylformamide(20 ml) was added potassium 2,3-dihydro-1H-isoindole-1,3-dione (7.0 g,37 mmol). After being stirred at 150° C. for 18 hours, the resultingmixture was then filtered and washed with diethyl ether (50 mL). Thefiltrate was washed with brine (50 mL×3), dried over sodium sulfate andconcentrated in vacuo. The residue was heated with stirring in water andthe precipitate was collected by filtration and dried in vacuo to afford6.0 g of the pure product as an orange solid (yield was 53%).

tert-Butyl [1-(2-aminoethyl)-cyclopropyl]carbamate

To a solution of tert-butyl1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]cyclopropylcarbamate(3.3 g, 2.4 mmol) in ethanol (100 mL) was added hydrazine hydrate (5 mL)and the resulting mixture was heated under reflux for 16 hours. Themixture was filtered and washed with diethyl ether. The filtrate wasconcentrated in vacuo to afford 1.5 g of the pure compound as an orangeoil (yield was 75%).

Intermediate 13 tert-Butyl [2-(1-aminocyclopropyl)ethyl]carbamate

Methyl 1-aminocyclopropanecarboxylate

To a solution of 1-aminocyclopropanecarboxylic acid (1.0 g, 9.9 mmol) inmethanol (30 mL) was added thionyl chloride (3.5 g, 29.7 mmol) at 0° C.The mixture was heated under reflux for 2 hours and then concentrated invacuo to afford 1.1 g of the crude product (yield was 100%).

Methyl 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylate

To a cooled mixture of methyl 1-aminocyclopropanecarboxylate (1.1 g, 9.6mmol) and an aqueous solution of potassium bicarbonate (2.88 g, 28.8mmol dissolved in 10 mL of water) in ethyl acetate (30 mL) was added asolution of di-tert-butyl dicarbonate (4.15 g, 19.2 mmol) in ethylacetate (10 mL) at 0° C. The reaction mixture was allowed to warm toroom temperature and stirred at this temperature overnight. Theseparated aqueous layer was extracted with ethyl acetate (20 mL). Thecombined organic layers were dried over sodium sulfate and concentratedin vauco to afford 2.0 g of the product (yield was 97%).

tert-Butyl [1-(hydroxymethyl)cyclopropyl]carbamate

To a cooled solution of methyl1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylate (1.2 g, 5.6 mmol)in tetrahydrofuran (10 mL) at 0° C. was added dropwise a solution oflithium borohydride (244 mg, 11.2 mmol) in tetrahydrofuran (10 mL) Thereaction mixture was allowed to warm to room temperature and stirred atthis temperature overnight. The reaction was quenched by addition ofwater (10 mL) and the resulting mixture was extracted withdichloromethane. The organic layer was dried over sodium sulfate andconcentrated in vacuo to afford 0.8 g of the product (yield was 76.2%).

tert-Butyl [1-(azidomethyl)cyclopropyl]carbamate

To a solution of tert-butyl [1-(hydroxymethyl)cyclopropyl]carbamate (1g, 5.3 mmol) in N,N-dimethylformamide (20 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (1.22 g, 8.0 mmol) anddiphenylphosphoryl azide (2.33 g, 8.00 mmol). After the mixture wasstirred at 80° C. for 3 hours, another batch of1,8-diazabicyclo[5.4.0]undec-7-ene (1.22 g, 8.0 mmol) anddiphenylphosphoryl azide (2.33 g, 8.00 mmol) was introduced and themixture was stirred at 80° C. for another 2 hours. The resulting mixturewas then diluted with water (20 mL) and extracted with ethyl acetate (30mL×2). The combined organic layers were used for next step directly.

tert-Butyl [1-(aminomethyl)cyclopropyl]carbamate

A solution of tert-butyl [1-(azidomethyl)cyclopropyl]carbamate (60 mL,obtained from the above step) was hydrogenated in the presence of 10%palladium on carbon (60 mg) at room temperature overnight under hydrogenatmosphere with hydrogen balloon. The reaction was filtered andconcentrated in vacuo to afford 40 mg of the crude product (yield was40%).

Intermediate 14 (1,1-Dioxidothietane-3,3-diyl)dimethanamine

3,3-Bis(azidomethyl)thietane

To a mixture of 3,3-bis(bromomethyl)thietane (15.0 g, 0.058 mol) andtetrabutylazanium bromide (0.93 g, 5%) in water (30 mL) was added sodiumazide (9.0 g, 0.138 mol). The mixture was stirred at 70° C. overnight,then diluted with water (20 mL) and extracted with dichloromethane (50mL×3). The combined organic layers were dried over sodium sulfate andconcentrated in vacuo to remove most of dichloromethane. The residualsolution (in 24 mL of dichloromethane) was used for the next step.

3,3-Bis-azidomethyl-thietane 1,1-dioxide

To a solution of 3,3-bis(azidomethyl)thietane (2.5 g, 13.59 mmol) in themixture of formic acid (5 mL) and dichloromethane (6 mL) was addedhydrogen peroxide (9.2 g, 81.54 mmol) slowly at 0° C. After being warmedslowly to room temperature and stirred at room temperature overnight,the mixture was diluted with water (10 mL) and extracted withdichloromethane (15 mL×3). The combined organic layers were dried oversodium sulfate and concentrated in vacuo. The residue was purified byflash column chromatography to afford 2.8 g of the desired product as awhite solid (yield of two steps was 96%).

(1,1-Dioxidothietane-3,3-diyl)dimethanamine

A solution of 3,3-bis-azidomethyl-thietane 1,1-dioxide (1.0 g, 4.63mmol) in methanol (10 mL) was stirred in the presence of 10% palladiumon carbon (0.2 g) under hydrogen atmosphere overnight. The resultingreaction mixture was filtered and the filtrate was concentrated in vacuoto afford 720 mg of the desired product.

Intermediate 15 Thietane-3,3-diyldimethanamine

A solution of 3,3-bis(azidomethyl)thietane (2.5 g, 13.59 mmol) indichloromethane (6 mL) and methanol (50 mL) was stirred in the presenceof 10% palladium on carbon (0.8 g) under 25 psi of hydrogen overnight.The resulting mixture was filtered and concentrated in vacuo to afford1.8 g of the desired product.

Intermediate 16 (3,3-Difluorocyclobutane-1,1-diyl)dimethanamine

Dipropan-2-yl 3,3-dimethoxycyclobutane-1,1-dicarboxylate

To a stirred suspension of sodium hydride (96.5 g, 2.413 mol, 60% inmineral oil) in dry N,N-dimethylformamide (900 ml) was added1,3-bis(propan-2-yl) propanedioate (363.3 g, 1.930 mol) dropwise undernitrogen at a rate such that the temperature was maintained below 70° C.On cessation of hydrogen evolution, the mixture was heated to 130° C.,to 3-dibromo-2,2-dimethoxypropane (252.8 g, 0.965 mol) was thenintroduced in one portion. The mixture was heated under reflux for 48hours. The cooled mixture was poured into a saturated aqueous solutionof ammonium chloride (300 mL) and extracted with methyl tert-butyl ether(300 mL). The organic layer was washed with a saturated aqueous solutionof sodium bicarbonate and brine, dried over sodium sulfate, andconcentrated in vacuo. The residue was distilled in vacuo (oil pump) toafford 52.7 g of dipropan-2-yl3,3-dimethoxycyclobutane-1,1-dicarboxylate as a colorless oil (yield was58.2%). ¹H NMR (400 MHz, CDCl₃) δ ppm 5.02 (m J=6.4 Hz, 2 H), 3.12 (s, 6H), 2.66 (s, 4 H), 1.11 (d, J=6.4 Hz, 12 H).

Dipropan-2-yl 3-oxocyclobutane-1,1-dicarboxylate

A solution of dipropan-2-yl 3,3-dimethoxycyclobutane-1,1-dicarboxylate(10.0 g, 34.6 mmol) in hydrochloric acid (3 N, 55 mL) was heated at 50°C. for 4 hours. The resulting mixture was neutralized with a saturatedaqueous solution of sodium bicarbonate and extracted with ethyl acetate(100 mL). The combined organic layers were dried over sodium sulfate andconcentrated in vacuo to afford 6.073 g of dipropan-2-yl3-oxocyclobutane-1,1-dicarboxylate as a light brown oil (yield was72.3%).

Dipropan-2-yl 3,3-difluorocyclobutane-1,1-dicarboxylate

To a cooled solution of dipropan-2-yl 3-oxocyclobutane-1,1-dicarboxylate(5.657 g, 23.3 mmol) in dichloromethane (50 ml) at −78° C., was addeddropwise a solution of N,N-diethylaminosuflur trifluoride (9.25 ml,70.05 mmol) in dichloromethane (25 ml) under nitrogen. After theaddition, the mixture was allowed to warm up to room temperature andstirred for 24 hours. The mixture was diluted with dichloromethane (50mL), and washed with 2 N aqueous solution of sodium hydroxide (50 mL)and brine (50 mL). The organic layer was dried over sodium sulfate, andconcentrated in vacuo to afford dipropan-2-yl3,3-difluorocyclobutane-1,1-dicarboxylate as a yellow oil (yield was68.8%).

3,3-Difluorocyclobutane-1,1-dicarboxylic acid

A mixture of 3,3-difluoro-cyclobutane-1,1-dicarboxylic acid diisopropylester (5.00 g, 18.9 mmol) and sodium hydroxide (3.00 g, 75.7 mmol) inmethanol (20 ml) was stirred at room temperature overnight. The formedoff-white solid was collected by filtration, washed with ethyl acetate,and dissolved in water. The aqueous solution was acidified withhydrochloric acid (3 N) to pH 3-4. The mixture was concentrated in vacuoto afford 6.293 g of the crude 3,3-difluorocyclobutane-1,1-dicarboxylicacid as a white solid, which was used for next step without furtherpurification.

3,3-Difluorocyclobutane-1,1-dicarboxamide

A solution of crude 3,3-difluorocyclobutane-1,1-dicarboxylic acid (6.293g) in thionyl chloride (50 mL) was heated under reflux for 2 hours. Thenthe solution was concentrated in vacuo to remove thionyl chloride. Tothe residue was added dropwise ice-cold ammonium hydroxide (10 mL) andstirred for 0.5 hour. The formed off-white precipitate was collected byfiltration. The filtrate was extracted with tetrahydrofuran (threetimes). The combined organic layers were dried over magnesium sulfateand concentrated in vacuo. The solids were combined to afford 1.858 g of3,3-difluorocyclobutane-1,1-dicarboxamide as an off-white solid (yieldof three steps was 55.2%).

(3,3-Difluorocyclobutane-1,1-diyl)dimethanamine

To a cooled solution of 3,3-difluorocyclobutane-1,1-dicarboxamide (1.858g, 10.4 mmol) in tetrahydrofuran (25 mL) at −10° C., was added slowlylithium aluminium hydride (2.375 g, 62.58 mmol). The reaction wasstirred at 0° C. for 4 hours and then heated under reflux for 30 hours.The mixture was cooled and quenched at 0° C. by addition of water (2.5mL), 15% aqueous solution of sodium hydroxide (7.5 mL) and water (2.5mL) successively. The resulting mixture was stirred at room temperaturefor 0.5 hour. The mixture was filtered and the filtrate was concentratedin vacuo to afford 1.137 g of the crude product of(3,3-difluorocyclobutane-1,1-diyl)dimethanamine as a colorless oil(yield was 72.8%).

Intermediate 173-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoylchloride

3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoic acid

A solution of phthalic ahydride (378 mg, 2.54 mmol) and3-amino-4,4,4-trifluorobutanoic acid (200 mg, 1.27 mmol) inN,N-dimethylformamide (5 mL) was heated at 160° C. under microwaveirradiation for 1 hour. The resulting mixture was cooled to roomtemperature, diluted with water, and extracted with ethyl acetate (30mL×2). The combined organic layers were washed with brine (50 mL), driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby flash chromatograph on silica gel (eluting with 50% ethyl acetate inhexane) to afford 270 mg of the product of3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoic acid(yield was 37%). MS obsd. (ESI⁺) [(M+H)⁺] 288.

3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoylchloride

To a solution of3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoic acid(270 mg, 0.94 mmol) in dichloromethane (10 mL) was added oxalyl chloride(0.16 mL, 1.88 mmol), followed by N,N-dimethylformamide (1 drop). Afterthe gas ceased to produce, the reaction mixture was stirred at roomtemperature for 2 hours. After the mixture was concentrated in vacuo,the residue was diluted with dichloromethane and concentrated in vacuoagain to afford 280 mg of the product (yield was 90%), which was usedfor next step without purification.

Intermediate 18 2-Fluorobutane-1,4-diamine

1,4-Dibromo-2-fluorobutane

To a solution of 1,4-dibromobutan-2-ol (6.0 g, 25.64 mmol) indichloromethane (80 mL) was added N,N-diethylaminosuflur trifluoride(6.25 mg, 38.79 mmol). The reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (15mL), washed with water (15 mL) and brine (15 mL), dried over sodiumsulfate, and concentrated in vacuo to afford 4.0 g of1,4-dibromo-2-fluoro-butane as a yellow oil.

2,2′-(2-Fluorobutane-1,4-diyl)bis(1H-isoindole-1,3(2H)-dione)

To a solution of 1,4-dibromo-2-fluoro-butane (4.0 g, 17.09 mmol) inN,N-dimethylformamide (60 mL) was added potassium2,3-dihydro-1H-isoindole-1,3-dione (9.5 g, 51.27 mmol). The reactionmixture was stirred at 100° C. overnight. The mixture was cooled to roomtemperature, diluted with ethyl acetate (60 mL), washed with water (60mL), brine (60 mL), dried over sodium sulfate, and concentrated in vacuoto afford 4.5 g of2,2′-(2-fluorobutane-1,4-diyl)bis(1H-isoindole-1,3(2H)-dione) as a whitesolid.

2-Fluorobutane-1,4-diamine

A mixture of2,2′-(2-fluorobutane-1,4-diyl)bis(1H-isoindole-1,3(2H)-dione) (1.0 g,2.73 mmol) and hydrazine hydrate (0.68 g, 13.6 mmol) in ethanol (20 mL)was heated under reflux for 16 hours. The resulting mixture was cooledto room temperature and concentrated in vacuo to afford the crudeproduct, which was used for the next step.

Intermediate 19 tert-Butyl(4S)-4-(aminomethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

tert-Butyl(4S)-4-[(benzylamino)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

A mixture of tert-butyl(4S)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.0 g, 4.36mmol), phenylmethanamine (491 mg, 4.58 mmol) and toluene (8 mL) washeated under reflux with stirring for 2 hours. The mixture wasconcentrated in vacuo. The residue was dissolved in 1,2-dichloroethane(10 mL), to which sodium bis(acetyloxy)boranuidyl acetate (2.31 g, 10.91mmol) was added. The mixture was stirred at room temperature for twodays, then diluted with water (25 mL), extracted with dichloromethane(25 mL×3). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by flash column chromatography to afford 849 mg of the product.

tert-Butyl(4S)-4-(aminomethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

A mixture of tert-butyl(4S)-4-[(benzylamino)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(810 mg, 2.53 mmol), palladium hydroxide on carbon (81 mg) and methanol(20 mL) was stirred at room temperature under hydrogen atmosphereovernight. The catalyst was removed by filtration. The filtrate wasconcentrated in vacuo. The residue was purified by SPE (12 mL tube, 2gram of DSC-SCX) to afford the pure product.

Intermediate 20 tert-Butyl 2-oxa-6-azaspiro[3.4]oct-8-ylcarbamate

6-Benzyl-8-nitro-2-oxa-6-aza-spiro[3.4]octane

To a solution of benzyl-methoxymethyl-trimethylsilanylmethyl-amine (3.0g, 12.6 mmol) and 3-nitromethylene-oxetane (1.38 g, 12.0 mmol) indichloromethane (60 mL) was added trifluoroacetic acid (0.93 mL, 12.6mmol) dropwise. The mixture was stirred at room temperature for 2 hours,quenched with sodium carbonate, extracted with dichloromethane. Theorganic layer was dried over sodium sulfate, concentrated in vacuo. Theresidue was purified by column chromatography on silica gel to give 2 gof product as colorless oil. It was used for next step without furtherpurification.

6-Benzyl-2-oxa-6-aza-spiro[3.4]oct-8-ylamine

The mixture of 6-benzyl-8-nitro-2-oxa-6-aza-spiro[3.4]octane (2 g, 8.1mmol), iron powder (2.3 g, 40.5 mmol), ammonium chloride (4.3 g, 81mmol), methanol (40 mL) and 8 mL of water was heated with stirring for 2hours at 80° C. The reaction mixture was filtered by a pad of celite.The filtrate was concentrated under reduced pressure, and the residuewas used for next step without further purification.

tert-Butyl (6-benzyl-2-oxa-6-azaspiro[3.4]oct-8-yl)carbamate

To a mixture of 6-benzyl-2-oxa-6-azaspiro[3.4]oct-8-ylamine (preparedabove), sodium carbonate (1.46 g, 13.74 mmol), dichloromethane (20 mL)and water (20 mL) was added di-tert-butyl dicarbonate (1.8 g, 8.24 mmol)at room temperature. The mixture was stirred at room temperatureovernight. The separated organic layer was dried over sodium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel to give 1.5 g of product as colorless oil,which was used for next step without further purification.

tert-Butyl 2-oxa-6-azaspiro[3.4]oct-8-ylcarbamate

To a solution of 6-benzyl-2-oxa-6-azaspiro[3.4]oct-8-ylamine (1.5 g,4.71 mmol) in methanol (50 mL) was added palladium hydroxide (20% oncarbon, 300 mg). After being stirred at room temperature for 4 hoursunder a hydrogen atmosphere, the resulting mixture was filtered. Thefiltrate was concentrated in vacuo to give 900 mg of the product ascolorless oil, which was used for next step without furtherpurification.

Intermediate 21 N-(3-Methylpyrrolidin-3-yl)-acetamide

N-(1-Benzyl-3-methylpyrrolidin-3-yl)-acetamide

To a solution of 1-benzyl-3-methylpyrrolidin-3-ol (1.0 g, 5.2 mmol) inacetonitrile (10 mL) at 0° C., was added concentrated sulfuric acid (10mL) slowly. After being stirred for 16 hours at room temperature, thereaction mixture was poured into ice-water. After the reaction mixturewas adjusted to pH 7 with a saturated aqueous solution of potassiumcarbonate, the resulting mixture was exacted with dichloromethane (200mL×3). The combined organic layers were dried over sodium sulfate, andconcentrated in vauo. The residue was purified by preparative HPLC toafford 600 mg of the product (yield was 50%).

N-(3-Methylpyrrolidin-3-yl)-acetamide

A mixture of N-(1-benzyl-3-methylpyrrolidin-3-yl)-acetamide (600 mg, 2.6mmol), palladium on carbon (400 mg, 10%) and ethanol (20 mL) was stirredat 40° C. under 50 Psi of hydrogen for 16 hours. The resulting mixturewas filtrated. The filtrate was concentrated in vacuo to give 200 mg ofthe desired product (yield was 54%), which was used for next stepwithout any purification.

Intermediate 22 2-Fluoropropane-1,3-diamine

2-Fluoropropanediamide

To a solution of 1,3-diethyl 2-difluoropropanedioate (25 g, 140.4 mmol)in methanol (100 mL) under a nitrogen atmosphere was added a solution ofammonia in methanol (80 mL, 7 N, 560 mmol). The resulting mixture wasstirred at room temperature overnight and then concentrated in vacuo.The residue was triturated in petroleum ether to afford 16.3 g of2-fluoropropanediamide as a white solid (yield was 97%). MS obsd. (ESI⁺)[(M+H)⁺] 121.

2-Fluoropropane-1,3-diamine

To a solution of 2-fluoropropanediamide (16.3 g, 136 mmol) intetrahydrofuran (200 mL) was added a solution of boran-tetrahydrofurancomplex (800 mL, 800 mmol, 1 M) in tetrahydrofuran. The reaction mixturewas heated at 70° C. with stirring overnight, then cooled in an icebath, stirred with methanol (100 mL) further for 30 minutes, andconcentrated in vacuo. The residue was dissolved in methanol (100 mL)and the solution was concentrated in vacuo. To the residue was addedwater (10 mL), potassium hydroxide was added with cooling until theaqueous solution was saturated. The mixture was extracted by diethylether (20 mL×2), and the combined organic layers was dried overpotassium hydroxide and concentrated in vacuo to afford 7.5 g of2-fluoropropane-1,3-diamine (yield was 60%). MS obsd. (ESI⁺) [(M+H)⁺]93.

Intermediate 23 Benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of 1-benzyloxycarbonyl-3-pyrroline (2.5 g) indichloromethane (60 mL) was added 3-chloroperoxybenzoic acid (6.08 g,50-60% purity). The reaction was stirred at room temperature for 72hours, and then a saturated sodium thiosulfate solution (50 mL) wasadded. After being stirred for additional 30 minutes, the mixture wasextracted with chloroform (50 mL×2). The combined organic layers werewashed successively with 2 N aqueous solution of sodium hydroxide (50mL×2) and brine (50 mL), dried over magnesium sulfate and concentratedin vacuo to afford 2.79 g of the crude benzyl6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate as an oil. MS obsd. (ESI⁺)[(M+H)⁺] 220.

trans-(±)-Benzyl-3-amino-4-hydroxypyrrolidine-1-carboxylate

A mixture of the crude benzyl6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate obtained in the above step(2.79 g) and 28% aqueous solution of ammonia (20 mL) was stirred at 40°C. for 2 days in a sealed tube, then 2 N aqueous solution of sodiumhydroxide (25 mL) was introduced and the mixture was extracted withchloroform (25 mL×3). The combined organic layers were dried overanhydrous magnesium sulfate and concentrated in vacuo to afford 2.67 gof the crude trans-benzyl-3-amino-4-hydroxypyrrolidine-1-carboxylate asoil. MS obsd. (ESI⁺) [(M+H)⁺] 237.

trans-(±)-Benzyl-3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate

To a cooled solution oftrans-benzyl-3-amino-4-hydroxypyrrolidine-1-carboxylate (2.67 g) inchloroform (25 mL) was added dropwise a solution of di-tert-butyldicarbonate (3.7 g) in chloroform (10 mL) in an ice-water bath, and themixture was stirred at room temperature for 19 hours. The reactionmixture was washed with water and the organic layer was dried overanhydrous magnesium sulfate and concentrated in vacuo. The residue waspurified by a column chromatography on silica gel to afford 2.7 g oftrans-benzyl-3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylateas crystals. MS obsd. (ESI⁺) [(M+H)⁺] 337.

trans-(±)-tert-Butyl [4-hydroxypyrrolidin-3-yl]carbamate

To a solution oftrans-3-tert-butoxycarbonylamino-4-hydroxy-pyrrolidine-1-carboxylic acidbenzyl ester (3.9 g) in methanol (31 mL) and tetrahydrofuran (7 mL) wasadded palladium hydroxide (20 wt % Pd on carbon, 500 mg) and the mixturewas stirred at room temperature under 40-45 psi of hydrogen atmosphereovernight. The resulting mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was triturated in the mixture ofethyl acetate and diisopropylether and filtered to remove the insoluablematerials. The filtrate was concentrated in vacuo to afford 2.0 g oftrans-tert-butyl [4-hydroxypyrrolidin-3-yl]carbamate (yield was 94%) asa powder. MS obsd. (ESI⁺) [(M+H)⁺] 203.

Intermediate 24 trans-(±)-Benzyl3-amino-4-fluoroypyrrolidne-1-carobxylate

trans-(±)-Benzyl 3-azido-4-fluoroypyrrolidne-1-carobxylate

In a solution of benzyl-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate(2.5 g) in methanol (20 mL) was added water (5 mL), ammonium chloride(550 mg) and sodium azide (1.5 g). The resulting mixture was heated at65° C. for 21 hours. The solids were removed by filtration and thefiltrate was concentrated in vacuo. The residue was poured into 15%aqueous solution of sodium hydroxide (30 mL) and extracted withdichloromethane (50 mL). The organic layers were washed with brine,dried over magnesium sulfate and concentrated in vacuo to afford 2.7 gof trans-(±)benzyl-3-azido-4-hydroxypyrrolidne-1-carobxylate. MS obsd.(ESI⁺) [(M+H)⁺] 250.

trans-(±)-Benzyl 3-azido-4-fluoroypyrrolidne-1-carobxylate

To a cooled solution oftrans-(±)benzyl-3-azido-4-hydroxypyrrolidne-1-carobxylate (6.5 g) indichloromethane (110 mL) was added diethylaminosulfur trifluoride (6.8mL) at −78° C. The mixture was stirred at room temperature for 16 hours,and then concentrated in vacuo. The residue was dissolved in ethylacetate (100 mL), and the solution was washed with a saturated sodiumbicarbonate (100 mL) and brine (100 mL), dried over magnesium sulfateand concentrated in vacuo. The residue was purified by columnchromatography on silica gel (eluting with 1% methanol indichloromethane) to yield 5.7 g oftrans-(±)benzyl-3-azido-4-fluoroypyrrolidne-1-carobxylate.

trans-(±)-Benzyl 3-amino-4-fluoroypyrrolidne-1-carobxylate

To a solution oftrans-(±)benzyl-3-azido-4-fluoroypyrrolidne-1-carobxylate (4.33 g) intetrahydrofuran (100 mL) and water (10 mL) was added triphenylphospine(4.5 g). The reaction mixture was heated under reflux for 2 hours. Thereaction mixture was concentrated in vacuo and the residue was dissolvedin ethyl acetate (50 mL). The solution was extracted with 15% aqueoussolution of citric acid (30 mL×2) and the aqueous layers were combined,basified with a concentrated aqueous ammonium hydroxide to about pH 9,then extracted with ethyl acetate (50 mL×2). The combined organic layerswere washed with brine (50 mL), dried over magnesium sulfate andconcentrated in vacuo to afford trans-(±)-benzyl3-amino-4-fluoroypyrrolidne-1-carobxylate.

Intermediate 25 trans-(±)-tert-Butyl (4-fluoropyrrolidin-3-yl)carbamate

trans-(±)-1-Benzyl-3-[(tert-butoxycarbonyl)amino]-4-fluoropyrrolidine-1-carboxylate

To a cooled solution oftrans-(±)-benzyl-3-amino-4-fluoroypyrrolidne-1-carobxylate (2.39 g) inchloroform (25 mL) was added dropwise a solution of di-tert-butyldicarbonate (3.7 g) in chloroform (10 mL) in an ice-water bath. Themixture was stirred at room temperature for 19 hours. The reactionmixture was washed with water and the organic layer was dried overanhydrous magnesium sulfate and concentrated in vacuo. The residue waspurified by a column chromatography on silica gel to afford 2.9 g oftrans-(±)-1-benzyl-3-[(tert-butoxycarbonyl)amino]-4-fluoropyrrolidine-1-carboxylate(yield was 90%) as crystals.

trans-(±)-tert-Butyl (4-fluoropyrrolidin-3-yl) carbamate

To a solution oftrans-(±)-1-benzyl-3-[(tert-butoxycarbonyl)amino]-4-fluoropyrrolidine-1-carboxylate(3.39 g) in methanol (31 mL) and tetrahydrofuran (7 mL) was addedpalladium hydroxide (20 wt % on carbon, 500 mg) and the mixture wasstirred at room temperature under 40-45 psi of hydrogen atmosphereovernight. The resulting mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was triturated in the mixture ofethyl acetate and diisopropylether and filtered to remove the insoluablematerials. The filtrate was concentrated in vacuo to afford 1.5 g oftrans-(±)-tert-butyl (4-fluoropyrrolidin-3-yl) carbamate (yield was 74%)as a powder.

Intermediate 26 tert-Butyl(4S)-4-ethenyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

3-tert-Butyl 4-methyl(4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate

A solution of methyl(2R)-2-{[(tert-butoxy)carbonyl]amino}-3-hydroxypropanoate (22 g, 0.1mol), 2,2-dimethoxypropane (20.8 g, 0.2 mol) and4-methylbenzene-1-sulfonic acid (0.5 g) in toluene was heated withstirring at 110° C. overnight. The solvent was removed under reducedpressure. The residue was treated with ethyl acetate, washed with waterand brine. The organic layer was dried over sodium sulfate, concentratedunder reduced pressure. The residue distilled at 0.6 mbar to give 16.5 gof 3-tert-butyl 4-methyl(4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (yield was 63.6%) asan amber oil.

tert-Butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a cooled solution of 3-tert-butyl 4-methyl(4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (16.5 g, 63.6 mmol)in dry dichloromethane (300 mL) at −78° C., was added a cooled solutionof 1.0 M diisobutylaluminium hydride in hexane (127.6 mL, 127.2 mmol)under argon. The rate of addition was adjusted so as to keep theinternal temperature below −65° C. and take about 1 hour to complete.The reaction mixture was stirred for an additional 2 hours at −78° C.under argon. The reaction was quenched by slowly adding 60 mL of coldmethanol (−78° C.) so as to keep the internal temperature below −65° C.The resulting mixture was extracted with ethyl acetate. The organiclayer was washed with brine, dried over sodium sulfate, concentratedunder reduced pressure. The residue was distilled at 0.7 mbar to givetert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (10g, 68.5%) as colorless liquid.

tert-Butyl (4S)-4-ethenyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a solution of methyltriphenylphosphonium bromide (3.1 g, 8.64 mmol)in dry tetrahydrofuran (30 mL) was add a solution of sodiumbis(trimethylsilyl)amide in hexane (1.0 M, 8.64 mL, 8.64 mmol) underargon. After the reaction was stirred for further 20 minutes, a solutionof (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.8 g, 7.86mmol) in dry tetrahydrofuran (20 mL) was added dropwise. The resultingmixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure. The residue was purified by flash columnto give tert-butyl(4S)-4-ethenyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.5 g, 83.9%)as colorless liquid.

Intermediate 27

Pyridazine-3-carboxamide

To a cooled solution of pyridazine-3-carboxylic acid (1.0 g, 8.06 mmol)in tetrahydrofuran (40 mL) in a dry-ice bath was added4-methyl-morpholine (0.9 g, 8.87 mmol) and isopropyl chloroformate (1.1g, 8.87 mmol) slowly. The reaction was stirred at −30° C. for 6 hours,then an aqueous solution of ammonia (8 mL, 10% W/W) was added. Theresulting mixture was stirred at room temperature overnight, washed witha saturated aqueous solution of potassium bisulfate (50 mL). The aqueouslayer was extracted with ethyl acetate (30 mL×3). The combined organiclayers were dried over sodium sulfate, filtered and concentrated invacuo to afford 202.5 mg of the desired product (yield was 20.4%). MSobsd. (ESI⁺) [(M+H)⁺] 124, ¹H NMR (400 MHz, CD₃OD) δ ppm 9.45-9.35 (t,J=1.6 Hz, 1 H), 8.58 (s, 1 H), 8.23-8.15 (d, J=7.6 Hz, 1 H), 7.98-7.88(m, 2 H).

Intermediate 28 Oxetane-3,3-diyldimethanamine

3,3-Bis-azidomethyl-oxetane

A mixture of 3,3-bis(bromomethyl)oxetane (25 g, 100 mmol) and sodiumazide (14.3 g, 220 mmol) in water (65 ml) was added tetrabutylazaniumbromide (1.61 g, 5 mmol). The reaction mixture was heated with stirringat 70° C. overnight. The reaction mixture was cooled to room temperatureand extracted with dichloromethane (50 mL×3). The combined organiclayers were washed with water, dried over sodium sulphate andconcentrated in vacuo to afford 18.7 g of 3,3-bis-azidomethyl-oxetane asa light yellow oil. The crude product was used for next step withoutfurther purification.

Oxetane-3,3-diyldimethanamine

A solution of 3,3-bis-azidomethyl-oxetane (18.7 g) in methanol (15 ml)was stirred in the presence of 10% palladium on carbon (1.8 g) underhydrogen atmosphere at room temperature for 5 hours. The reactionmixture was filtered and the filtrate was concentrated in vacuo toafford oxetane-3,3-diyldimethanamine (12 g) as a light yellow solid.

Intermediate 29 Oxetan-3-ylidene-acetonitrile

To a solution of oxetan-3-one (5 g, 69.4 mmol) in dry dichloromethane(150 ml) was added (triphenylphosphoranylidene)acetonitrile (20.9 g,69.4 mmol) at room temperature. After being stirred for 6 hours, themixture was concentrated in vacuo and the residue was filtered through apad of silica gel (eluting with 30-50% diethyl ether in pentanes) toafford 5.2 g of oxetan-3-ylidene-acetonitrile as a white solid (yieldwas 79%).

3-(Benzylamino)oxetan-3-acetonitrile

A mixture of oxetan-3-ylidene-acetonitrile (950 mg, 10 mmol) andphenylmethanamine (1.31 ml, 12 mmol) was heated with stirring at 60° C.for 5 hours under nitrogen. The mixture was concentrated in vacuo. Theresidue was purified by flash column (eluting with 0-50% ethyl acetatein hexane) to afford 1.65 g of 3-(benzylamino)oxetan-3-acetonitrile as acolorless oil (yield was 81.7%).

3-(Aminoethyl)-N-benzyloxetan-3-amine

To a cooled slurry of lithium aluminium hydride (327 mg, 8.6 mmol) inanhydrous diethyl ether (40 mL), was added a solution of3-(benzylamino)oxetan-3-acetonitrile (1.0 g, 4.3 mmol) in anhydrousdiethyl ether (10 mL) dropwise at 0° C. After being stirred at 0° C. for2 hours, the reaction was quenched by introducing disodium sulfatedecahydrate slowly. After being stirred for 30 minutes, the mixture wasfiltered, and the filter cake was washed with ethyl acetate. Thefiltrate was dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by flash column to afford 800 mg of3-(aminoethyl)-N-benzyloxetan-3-amine as a light yellow oil (yield was79%).

Intermediate 30

The intermediate was prepared in analogy to1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone inIntermediate 4 by oxidation of3-(aminomethyl)-N,N-dibenzylthietan-3-amine (Intermediate 9-4) with3-chloroperoxybenzoic acid.

The following examples were prepared by the general methods outlined inthe schemes above. They are intended to illustrate the meaning of thepresent invention but should by no means represent a limitation withinthe meaning of the present invention.

Example 1-1N-[(3-Aminooxetan-3-yl)methyl]-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

4-(4-Chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine

A mixture of 8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.63 g,3.2 mmol), 2,4-dichloro-6-methylquinoline (0.68 g, 3.2 mmol) andn-butanol (4 mL) was heated with stirring in a 5 mL of microwave processvial for 2.5 hours at 160° C. under microwave irradiation. The solventwas removed by concentration in vacuo. The residue was dissolved in amixture solvent of ethanol and dichloromethane and then concentrated invacuo to remove dichloromethane. The formed precipitate was collected byfiltration, which was washed with diethyl ether and petroleum ether,dried in vacuo to afford 0.59 g of the product as a pale white solid(yield was 50%). MS obsd. (ESI⁺) [(M+H)⁺] 371.

4-(4-Chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine(0.40 g, 1.1 mmol) and sodium metaperiodate (0.71 g, 3.3 mmol) inmethanol (15 mL) and water (6 mL) was stirred for 12 hours at roomtemperature. After removal of the solvent by concentration in vacuo, theresidue was dissolved in methanol (15 mL). A solution of potassiumpermanganate (0.17 g, 1.1 mmol) in water (6 mL) was added dropwise tothe above solution which was cooled to 0° C. After being stirred for 2hours at 0° C., the mixture was extracted with ethyl acetate (10 mL).The organic layer was filtered through a short silica gel column. Thefiltrate was concentrated in vacuo to afford 0.40 g of the product as awhite solid (yield was 90%). MS obsd. (ESI⁺) [(M+H)⁺] 403.

N-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (50 mg, 0.13 mmol), cesium carbonate (80 mg, 0.26 mmol),palladium acetate (2.8 mg, 0.013 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (11 mg, 0.019 mmol) and3-(aminomethyl)-N,N-dibenzyloxetan-3-amine (54 mg, 0.19 mmol) in toluene(5 mL) was heated with stirring for 4 hours at 120° C. After beingcooled to room temperature, the mixture was concentrated in vacuo. Theresidue was purified by flash chromatography (eluting with 0.5%triethylamine and 5% methanol in dichloromethane) to afford 50 mg of theproduct as a white powder (yield was 59%). MS obsd. (ESI⁺) [(M+H)⁺] 649.N-[(3-Aminooxetan-3-yl)methyl]-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A mixture ofN-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(50 mg, 0.077 mmol), 10% palladium hydroxide on carbon (100 mg) andtrifluoroacetic acid (0.2 mL) in methanol (20 mL) was stirred for 12hours at room temperature under hydrogen atmosphere (1 bar). Theresulting mixture was basified with a saturated aqueous solution ofsodium bicarbonate to pH >9 and then extracted with dichloromethane (20mL×2). The combined organic layers were dried over anhydrous sodiumsulfate, and then concentrated in vacuo. The residue was purified bypreparative HPLC to afford 10 mg of the product (yield was 28%). MSobsd. (ESI⁺) [(M+H)⁺] 469, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.82 (d, J=8.34Hz, 2 H), 7.56 (brs, 2 H), 7.44 (brs, 1 H), 7.18 (d, J=8.59 Hz, 1 H),6.22 (s, 1 H), 5.27-5.13 (m, 2 H), 4.74-4.55 (m, 4 H), 4.50 (brs, 2 H),3.86 (s, 3 H), 3.81-3.72 (m, 2 H), 3.71-3.60 (m, 2 H), 2.46 (s, 3 H).

Example 1-2N-[(3-Aminooxetan-3-yl)methyl]-2-(8-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 1-1 in Scheme 4 byusing 2,4-dichloro-6-methylquinoline,8-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]457, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.95 (dd, J=8.46, 5.18 Hz, 1 H),7.77-7.64 (m, 2 H), 7.47 (d, J=8.34 Hz, 1 H), 7.43-7.25 (m, 2 H), 6.20(s, 1 H), 5.19 (brs, 2 H), 4.68-4.57 (m, 6 H), 3.70 (s, 2 H), 3.67-3.56(m, 2 H), 2.44 (s, 3 H).

Example 1-3N-[(3-Aminooxetan-3-yl)methyl]-2-(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 1-1 in Scheme 4 byusing 2,4-dichloro-6-methylquinoline,7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]457, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.02 (dd, J=8.72, 5.43 Hz, 1 H),7.79-7.65 (m, 2 H), 7.46 (d, J=8.34 Hz, 1 H), 7.33 (d, J=8.84 Hz, 1 H),7.17 (td, J=8.40, 2.65 Hz, 1 H), 6.17 (s, 1 H), 5.17 (brs, 2 H),4.68-4.41 (m, 6 H), 3.72-3.64 (m, 2 H), 3.64-3.53 (m, 2 H), 2.44 (s, 3H).

Example 1-4N-[(3-Aminooxetan-3-yl)methyl]-2-(9-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 1-1 in Scheme 4 byusing 2,4-dichloro-6-methylquinoline,9-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]457, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.75-7.65 (m, 2 H), 7.60 (td, J=7.96,4.80 Hz, 1 H), 7.46 (d, J=8.34 Hz, 1 H), 7.32 (dd, J=8.59, 1.77 Hz, 1H), 7.17 (dd, J=10.36, 8.34 Hz, 1 H), 6.15 (s, 1 H), 5.20 (s, 2 H),4.68-4.53 (m, 4 H), 4.45 (brs, 2 H), 3.86-3.73 (m, 2 H), 3.65 (s, 2 H),2.43 (s, 3 H).

Example 1-5N-[(3-Aminooxetan-3-yl)methyl]-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 1-1 in Scheme 4 byusing 2,4-dichloro-6-methylquinoline,7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]469, ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (d, J=8.84 Hz, 1 H), 7.68 (s,1 H), 7.57 (d, J=2.53 Hz, 1 H), 7.34 (d, J=8.59 Hz, 1 H), 7.30-7.21 (m,1 H), 6.96 (dd, J=8.72, 2.65 Hz, 1 H), 6.35 (t, J=5.31 Hz, 1 H), 6.19(s, 1 H), 5.04 (brs, 2 H), 4.45-4.39 (m, 6 H), 3.92-3.75 (m, 3 H),3.62-3.45 (m, 4 H), 2.37 (s, 3 H).

Example 1-6N-[(3-Aminooxetan-3-yl)methyl]-2-(8-chloro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 1-1 in Scheme 4 byusing 2,4-dichloro-6-methylquinoline,8-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine and3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]473, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.99-7.88 (m, 2 H), 7.77 (s, 1 H),7.64 (dd, J=8.08, 2.27 Hz, 1 H), 7.53 (d, J=8.59 Hz, 1 H), 7.40 (d,J=8.59 Hz, 1 H), 6.19 (s, 1 H), 5.21 (brs, 2 H), 4.84-4.56 (m, 4 H),4.53 (brs, 2 H), 3.75 (s, 2 H), 3.68 (brs, 2 H), 2.45 (s, 3 H).

Example 1-7N-[(3-Aminooxetan-3-yl)methyl]-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-4-amine

The title compound was prepared in analogy to Example 1-1 in Scheme 4 byusing 2,4-dichloroquinoline,7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]455, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.79 (d, J=8.84 Hz, 1 H), 7.68 (s, 1H), 7.57 (d, J=2.53 Hz, 1 H), 7.34 (d, J=8.59 Hz, 1 H), 7.30-7.21 (m, 1H), 6.96 (dd, J=8.72, 2.65 Hz, 1 H), 6.35 (t, J=5.31 Hz, 1 H), 6.19 (s,1 H), 5.04 (brs, 2 H), 4.45 (d, J=5.81 Hz, 2 H), 4.39 (d, J=5.81 Hz, 2H), 3.92-3.75 (m, 3 H), 3.62-3.45 (m, 4 H), 2.37 (s, 3 H).

Example 2-1N-[(3-Aminotetrahydrofuran-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

N-{[3-(Dibenzylamino)tetrahydrofuran-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

To a mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (400 mg, 1.08 mmol, prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 1-1 by using2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloro-6-methylquinoline), 3-(aminomethyl)-N,N-dibenzyltetrahydrofuran-3-amine (385 mg, 1.3 mmol), sodium tert-butoxide (207mg, 2.16 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (50 mg) and1,1′-bis(diphenylphosphino)ferrocene (200 mg) in 1,4-dioxane (5 mL) washeated with stirring in a sealed 10 mL of microwave process vial for 1hour at 120° C. under microwave irradiation. The resulting mixture wasconcentrated in vacuo. The residue was purified by preparative HPLC toafford 270 mg of the desired product (yield was 39.7%).

N-[(3-Aminotetrahydrofuran-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A mixture ofN-{[3-(dibenzylamino)tetrahydrofuran-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(270 mg, 0.43 mmol), 10% palladium hydroxide on active carbon (300 mg)in methanol (20 mL) was stirred for 16 hours at room temperature underhydrogen atmosphere (1 bar). The resulting mixture was concentrated invacuo. The residue was purified by preparative HPLC to afford 21 mg ofthe desired product (yield was 10.8%). MS obsd. (ESI⁺) [(M+H)⁺] 453, ¹HNMR (400 MHz, CD₃OD) δ ppm 8.06-7.98 (m, 2 H), 7.89-7.87 (d, J=7.6 Hz, 1H), 7.75-7.66 (m, 2 H), 7.59-7.56 (m, 2 H), 6.22-6.20 (d, J=8.4 Hz, 1H), 5.35 (s, 2 H), 4.5 (s, 2 H), 4.08-3.97 (m, 4 H), 3.88-3.73 (m, 3 H),2.81 (s, 2 H), 2.46 (s, 3 H), 2.31 (s, 2 H).

Example 2-2 N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 2-1 in Scheme 4 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]439, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (dd, J=1.2, 7.6 Hz, 1 H), 7.90(d, J=6.8 Hz, 1 H), 7.66 (s, 1 H), 7.62 (td, J=1.2, 7.6 Hz, 1 H),7.47-7.43 (m, 2 H), 7.30 (dd, J=1.6, 8.4 Hz, 1 H), 6.20 (s, 1 H), 5.18(s, 2 H), 4.63 (d, J=6.4 Hz, 2 H), 4.59 (d, J=6.8 Hz, 2 H), 4.59 (brs, 2H), 3.68 (s, 2 H), 3.59 (t, J=4.4 Hz, 2 H), 2.42 (s, 3 H).

Example 2-3N-[(4-Aminotetrahydro-2H-pyran-4-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 2-1 in Scheme 4 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and4-(aminomethyl)-N,N-dibenzyltetrahydro-2H-pyran-4-amine. MS obsd. (ESI⁺)[(M+H)⁺] 467, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (d, J=7.2 Hz, 1 H),7.87 (d, J=7.6 Hz, 1 H), 7.68 (s, 1 H), 7.64-7.60 (m, 1 H), 7.44 (m, 2H), 7.29 (dd, J=2.0, 8.4 Hz, 1 H), 6.14 (s, 1 H), 5.16 (s, 2 H), 4.54(brs, 2 H), 3.86-3.74 (m, 4 H), 3.58 (t, J=4.8 Hz, 2 H), 2.42 (s, 3 H),2.18 (dd, J=2.4, 4.8 Hz, 2 H), 1.88-1.81 (m, 2 H), 1.57 (m, 2 H).

Example 2-4N-[(3-Aminooxetan-3-yl)methyl]-2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-4-amine

The title compound was prepared in analogy to Example 2-1 in Scheme 4 byusing4-(4-chloroquinolin-2-yl)-8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloroquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine.MS (ESI⁺) [(M+H)⁺] 439, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.91 (d, J=8.34Hz, 1 H), 7.84 (d, J=7.58 Hz, 1 H), 7.72-7.60 (m, 1 H), 7.49-7.35 (m, 3H), 7.09 (ddd, J=8.21, 5.18, 3.03 Hz, 1 H), 6.52 (t, J=5.43 Hz, 1 H),6.22 (s, 1 H), 5.06 (brs, 2 H), 4.45 (d, J=6.06 Hz, 3 H), 4.38 (d,J=6.06 Hz, 3 H), 3.61 (t, J=4.80 Hz, 2 H), 3.56 (d, J=5.31 Hz, 2 H),2.31 (s, 3 H).

Example 2-5N-[(3-Aminooxetan-3-yl)methyl]-6-methyl-2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 2-1 in Scheme 4 byusing4-(4-chloro-6-methylquinolin-2-yl)-8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloro-6-methylquinoline) and3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]453, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.82 (d, J=7.83 Hz, 1 H), 7.68 (d,J=3.03 Hz, 2 H), 7.41 (d, J=6.57 Hz, 1 H), 7.33 (d, J=8.59 Hz, 1 H),7.25 (dd, J=8.59, 1.52 Hz, 1 H), 6.42 (t, J=5.56 Hz, 1 H), 6.19 (s, 1H), 5.05 (brs, 2 H), 4.45 (d, J=5.81 Hz, 3 H), 4.39 (d, J=6.06 Hz, 3 H),3.60 (t, J=4.55 Hz, 2 H), 3.55 (d, J=5.31 Hz, 2 H), 2.37 (s, 3 H), 2.31(s, 3 H).

Example 2-62-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(2-oxa-6-azaspiro[3.4]oct-8-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 2-1 in Scheme 4 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and6-benzyl-2-oxa-6-azaspiro[3.4]oct-8-ylamine. MS obsd. (ESI⁺) [(M+H)⁺]465, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.11-8.08 (m, 2 H), 7.90-7.88 (d,J=7.2, 1 H), 7.75-7.70 (m, 2 H), 7.65-7.59 (m, 2 H), 6.36 (s, 1 H),5.38-5.36 (d, J=8.8, 2 H), 5.20-5.10 (m, 1 H), 4.80-4.79 (m, 2 H),4.74-4.72 (m, 2 H), 4.56-4.54 (d, J=7.2, 2 H), 3.90-3.87 (m, 1 H),3.81-3.75 (m, 4 H), 3.60-3.50 (m, 1 H), 2.48 (s, 3 H).

Example 2-7N-[2-(3-Aminooxetan-3-yl)ethyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 2-1 in Scheme 4 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and3-(aminoethyl)-N-benzyloxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 453, ¹HNMR (400 MHz, DMSO-d6) δ ppm 7.95-7.89 (t, 1 H), 7.89-7.87 (t, 1 H),7.64-7.60 (m, 2 H), 7.49-7.45 (m, 1 H), 7.31 (d, J=8.4 Hz, 1 H),7.24-7.21 (m, 1 H), 6.87 (t, J=10.4 Hz, 1 H), 6.05 (s, 1 H), 5.08 (s, 2H), 4.39 (m, 6 H), 3.63 (t, J=9.2 Hz, 2 H), 3.41-3.36 (m, 2 H), 2.41 (s,2 H), 2.35 (s, 3 H), 2.08 (t, J=14.4 Hz, 2 H).

Example 2-8N-[(3-Aminooxetan-3-yl)methyl]-6-methyl-2-(5-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 2-1 in Scheme 4 byusing4-(4-chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloro-6-methylquinoline) and3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]453, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.03 (dd, J=7.96, 1.39 Hz, 1 H), 7.90(d, J=6.57 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.46 (ddd, J=8.15, 6.63, 1.64Hz, 2 H), 7.33 (dd, J=8.59, 1.77 Hz, 1 H), 6.15 (s, 1 H), 5.86 (d,J=6.82 Hz, 1 H), 4.64-4.53 (m, 4 H), 4.40-4.25 (brs, 2 H), 3.70 (d,J=8.59 Hz, 1 H), 3.62-3.58 (m, 2 H), 3.57-3.49 (m, 1 H), 2.43 (s, 3 H),2.00 (d, J=7.07 Hz, 3 H).

Example 2-9N-[(3-Aminooxetan-3-yl)methyl]-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 2-1 in Scheme 4 byusing4-(4-chloroquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloroquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine.MS obsd. (ESI⁺) [(M+H)⁺] 455, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.91-7.74(m, 2 H), 7.58-7.38 (m, 3 H), 7.22-7.03 (m, 2 H), 6.23 (s, 1 H), 5.12(brs, 2 H), 4.70-4.46 (m, 6 H), 3.81 (s, 3 H), 3.70 (s, 2 H), 3.65-3.52(m, 2 H).

Example 2-10N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-amine

The title compound was prepared in analogy to Example 2-1 in Scheme 4 byusing4-(4-chloro-1,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloro-1,6-naphthyridine) and3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]426, ¹H NMR (400 MHz, CD₃OD) δ ppm 9.15 (s, 1 H), 8.28-8.80 (d, J=6.4Hz, 1 H), 8.00-7.95 (d, J=1.2 Hz, 1 H), 7.95-7.90 (d, J=7.2 Hz, 1 H),7.62-7.58 (t, J=0.8 Hz, 1 H), 7.50-7.40 (m, 2 H), 6.31 (s, 1 H), 5.35(s, 2 H), 4.65-4.58 (m, 6 H), 3.80 (s, 2 H), 3.60-3.50 (t, J=2.8 Hz, 2H).

Example 2-11 N-[(1-Aminocyclohexyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 2-1 in Scheme 4 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and1-(aminomethyl)-N,N-dibenzylcyclohexanamine. MS obsd. (ESI⁺) [(M+H)⁺]465, ¹H NMR (400 MHz, CDCl₃) δ ppm 8.02-7.99 (dd, J=1.2 Hz, 8.0 Hz, 1H), 7.65-7.63 (d, J=7.6 Hz, 1 H), 7.48-7.46 (m, 2 H), 7.34-7.25 (m, 3H), 5.86 (s, 1 H), 5.64 (s, 1 H), 5.10 (s, 2 H), 4.56 (s, 2 H), 3.55 (s,2 H), 3.05-3.04 (d, J=4.8 Hz, 2 H), 2.41 (s, 3 H), 1.98 (s, 4 H), 1.56(m, 10 H).

Example 3-1N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(8-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A mixture of8-(4-chloro-6-methylquinolin-2-yl)-8-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (200 mg, 0.51 mmol, prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using8-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloro-6-methylquinoline), sodium tert-butoxide (96 mg, 1.02mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (42mg, 0.051 mmol), 1,1′-bis(diphenylphosphino)ferrocene (29 mg, 0.051mmol), and oxetane-3,3-diyldimethanamine (89 mg, 0.77 mmol) in1,4-dioxane (2 mL) was heated with stirring in a sealed 5 mL ofmicrowave process via for 1.5 hours at 120° C. under microwaveirradiation. The resulting mixture was concentrated in vacuo. Theresidue was purified by preparative HPLC to afford 48 mg of the productas a white product (yield was 20%). MS obsd. (ESI⁺) [(M+H)⁺] 471, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.95 (dd, J=8.34, 5.05 Hz, 1 H), 7.74 (t, J=5.56Hz, 2 H), 7.54 (d, J=8.59 Hz, 1 H), 7.46-7.29 (m, 2 H), 6.19 (s, 1 H),5.23 (brs, 2 H), 4.69-4.58 (m, 8 H), 3.78 (s, 2 H), 3.69 (brs, 2 H),3.41 (s, 2 H), 2.46 (s, 3 H).

Example 3-2N-{[3-(Benzylamino)oxetan-3-yl]methyl}-6-chloro-2-(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4,6-trichloroquinoline) and 3-(aminomethyl)-N-benzyloxetan-3-amine. MSobsd. (ESI⁺) [(M+H)⁺] 567, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (dd,J=8.72, 5.43 Hz, 1 H), 7.82 (d, J=2.27 Hz, 1 H), 7.71 (dd, J=9.09, 2.53Hz, 1 H), 7.50 (d, J=8.84 Hz, 1 H), 7.39 (dd, J=8.84, 2.27 Hz, 1 H),7.33 (d, J=7.07 Hz, 2 H), 7.25-7.16 (m, 2 H), 7.16-7.04 (m, 2 H), 6.13(s, 1 H), 5.15 (brs, 2 H), 4.71 (d, J=6.57 Hz, 2 H), 4.54 (d, J=6.57 Hz,4 H), 3.77 (s, 2 H), 3.72 (s, 2 H), 3.56 (t, J=4.93 Hz, 2 H).

Example 3-3N-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 3-2) and3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 477, ¹H NMR (400MHz, CD₃OD) δ ppm 8.07-7.94 (m, 2 H), 7.72 (dd, J=8.97, 2.65 Hz, 1 H),7.53 (d, J=8.84 Hz, 1 H), 7.43 (dd, J=8.84, 2.27 Hz, 1 H), 7.15 (td,J=8.46, 2.53 Hz, 1 H), 6.23 (s, 1 H), 5.18 (brs, 2 H), 4.73-4.60 (m, 4H), 4.51 (brs, 2 H), 3.75 (s, 2 H), 3.59 (t, J=4.67 Hz, 2 H).

Example 3-4N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloroquinolin-2-yl)-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloroquinoline) and oxetane-3,3-diyldimethanamine. MS obsd.(ESI⁺) [(M+H)⁺] 469, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.41 (brs, 3 H), 8.02(d, J=8.08 Hz, 1 H), 7.97 (d, J=8.84 Hz, 1 H), 7.68 (d, J=8.08 Hz, 1 H),7.60 (t, J=7.71 Hz, 1 H), 7.44 (d, J=2.53 Hz, 1 H), 7.31 (t, J=7.20 Hz,1 H), 7.01 (dd, J=8.59, 2.53 Hz, 1 H), 6.19 (s, 1 H), 5.20 (br. s, 2 H),4.64 (s, 4 H), 4.54 (brs, 2 H), 3.92 (s, 3 H), 3.81 (s, 2 H), 3.69-3.55(m, 2 H), 3.47 (s, 2 H).

Example 3-5N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloro-6-methylquinoline) and oxetane-3,3-diyldimethanamine. MSobsd. (ESI⁺) [(M+H)⁺] 483, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.89 (d, J=8.59Hz, 1 H), 7.64 (s, 1 H), 7.51-7.39 (m, 2 H), 7.31 (dd, J=8.59, 1.77 Hz,1 H), 6.91 (dd, J=8.59, 2.53 Hz, 1 H), 6.14 (s, 1 H), 5.10 (brs, 2 H),4.69-4.44 (m, 6 H), 3.90 (s, 3 H), 3.74-3.61 (m, 2 H), 3.57-3.52 (m, 2H), 3.18 (s, 2 H), 2.42 (s, 3 H).

Example 3-6N-{[3-({[2-(7-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}methyl)oxetan-3-yl]methyl}acetamide

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloro-6-methylquinoline) andN-{[3-(aminomethyl)oxetan-3-yl]methyl}acetamide. MS obsd. (ESI⁺)[(M+H)⁺] 525, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.91 (d, J=8.59 Hz, 1 H),7.70 (s, 1 H), 7.47 (d, J=8.59 Hz, 1 H), 7.41 (d, J=2.27 Hz, 1 H), 7.33(dd, J=8.46, 1.64 Hz, 1 H), 6.94 (d, J=8.59 Hz, 1 H), 6.18 (s, 1 H),5.12 (s, 2 H), 4.61-4.54 (m, 6 H), 3.90 (s, 3 H), 3.68 (s, 2 H),3.67-3.63 (m, 2 H), 3.59-3.51 (m, 2 H), 2.44 (s, 3 H), 2.05 (s, 3 H).

Example 3-7N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloroquinolin-2-yl)-8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloroquinoline) and oxetane-3,3-diyldimethanamine. MS obsd.(ESI⁺) [(M+H)⁺] 453, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.86-7.69 (m, 3 H),7.57-7.49 (m, 1 H), 7.47-7.34 (m, 2 H), 7.19-7.06 (m, 1 H), 6.17 (s, 1H), 5.11 (brs, 2 H), 4.68-4.39 (m, 6 H), 3.67 (s, 2 H), 3.63 (q, J=7.07Hz, 1 H), 3.55 (t, J=4.55 Hz, 2 H), 3.15 (s, 2 H), 2.33 (s, 3 H).

Example 3-8N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloro-6-methylquinoline) and oxetane-3,3-diyldimethanamine. MSobsd. (ESI⁺) [(M+H)⁺] 467, ¹H NMR (400 MHz, CD₃OD) 7.74-7.62 (m, 2 H),7.58 (s, 1 H), 7.43 (d, J=8.59 Hz, 1 H), 7.32-7.20 (m, 2 H), 6.07 (s, 1H), 4.99 (brs, 2 H), 4.62-4.48 (m, 4 H), 4.48-4.18 (m, 2 H), 3.65-3.60(m, 2 H), 3.44 (brs, 2 H), 3.11 (s, 2 H), 2.43-2.26 (m, 3 H), 2.14 (s, 3H).

Example 3-9[3-({[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}methyl)oxetan-3-yl]methanol

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and3-(aminomethyl)oxetan-3-yl]methanol. MS obsd. (ESI⁺) [(M+H)⁺] 454, ¹HNMR (400 MHz, CD₃OD) δ ppm 8.02-7.96 (m, 1 H), 7.90 (d, J=7.33 Hz, 1 H),7.68-7.54 (m, 2 H), 7.45 (d, J=8.34 Hz, 2 H), 7.35-7.20 (m, 1 H), 6.19(s, 1 H), 5.14 (s, 2 H), 4.60 (d, J=6.06 Hz, 3 H), 4.51 (d, J=6.06 Hz, 3H), 3.98 (s, 2 H), 3.67 (s, 2 H), 3.58 (t, J=4.67 Hz, 2 H), 2.42 (s, 3H).

Example 3-10(2S)-3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(2S)-3-aminopropane-1,2-diol. MS obsd. (ESI⁺) [(M+H)⁺] 428, ¹H NMR (400MHz, CD₃OD) δ ppm 7.98 (dd, J=7.83, 1.26 Hz, 1 H), 7.89 (d, J=7.33 Hz, 1H), 7.63 (td, J=7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50-7.35 (m, 2 H),7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55(brs, 2 H), 4.04-3.89 (m, 1 H), 3.69 (d, J=5.56 Hz, 2 H), 3.64-3.49 (m,4 H), 2.41 (s, 3 H).

Example 3-11(2R)-3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(2R)-3-aminopropane-1,2-diol. MS obsd. (ESI⁺) [(M+H)⁺] 428, ¹H NMR (400MHz, CD₃OD) δ ppm 7.98 (dd, J=7.83, 1.26 Hz, 1 H), 7.89 (d, J=7.33 Hz, 1H), 7.63 (td, J=7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50-7.35 (m, 2 H),7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55(brs, 2 H), 4.04-3.89 (m, 1 H), 3.69 (d, J=5.56 Hz, 2 H), 3.64-3.49 (m,4 H), 2.41 (s, 3 H).

Example 3-12N-{[1-(Aminomethyl)-3,3-difluorocyclobutyl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(3,3-difluorocyclobutane-1,1-diyl)dimethanamine. MS obsd. (ESI⁺)[(M+H)⁺] 487, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.11 (dd, J=7.83, 1.01 Hz, 1H), 8.08 (s, 1 H), 7.89 (d, J=7.07 Hz, 1 H), 7.80-7.68 (m, 2 H),7.68-7.56 (m, 2 H), 6.15 (s, 1 H), 5.37 (s, 2 H), 4.55 (brs, 2 H), 3.80(s, 2 H), 3.79-3.67 (m, 2 H), 3.44 (s, 2 H), 2.76 (t, J=12.25 Hz, 4 H),2.51 (s, 3 H).

Example 3-13N-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4,6-trichloroquinoline) and 3-(aminomethyl)oxetan-3-amine. MS obsd.(ESI⁺) [(M+H)⁺] 489, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.95 (d, J=2.27 Hz, 1H), 7.83-7.74 (m, 1 H), 7.58-7.44 (m, 2 H), 7.44-7.33 (m, 1 H), 7.14(dd, J=8.34, 2.78 Hz, 1 H), 6.24 (s, 1 H), 5.11 (brs, 2 H), 4.61 (q,J=6.74 Hz, 6 H), 3.82 (s, 3 H), 3.69 (s, 2 H), 3.63-3.50 (m, 2 H), 2.05(s, 2 H).

Example 3-14N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 3-13) andoxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 503, ¹H NMR (400MHz, CD₃OD) δ ppm 8.23 (s, 1 H), 7.88 (d, J=8.59 Hz, 1 H), 7.73 (d,J=8.84 Hz, 1 H), 7.65-7.51 (m, 2 H), 7.21 (dd, J=8.34, 2.78 Hz, 1 H),6.30 (s, 1 H), 5.26 (brs, 2 H), 4.76-4.60 (m, 6 H), 4.56 (brs, 1 H),3.91 (s, 2 H), 3.85 (s, 3 H), 3.69 (brs, 2 H), 3.52 (s, 2 H).

Example 3-15trans-N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclohexane-1,2-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andtrans-cyclohexane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 451, ¹H NMR (400MHz, CD₃OD) δ ppm 8.06-7.96 (d, J=7.8 Hz, 1 H), 7.83 (d, J=7.33 Hz, 1H), 7.70 (s, 1 H), 7.60 (td, J=7.52, 1.14 Hz, 1 H), 7.50-7.38 (m, 2 H),7.28 (dd, J=8.46, 1.64 Hz, 1 H), 6.13 (s, 1 H), 5.20-5.11 (m, 2 H),3.72-3.60 (m, 1 H), 3.58-3.49 (m, 1 H), 3.42-3.35 (m, 2 H), 3.35-3.30(m, 1 H), 2.87 (td, J=10.17, 3.92 Hz, 1 H), 2.42 (s, 3 H), 2.10 (d,J=5.31 Hz, 1 H), 2.01 (d, J=13.14 Hz, 1 H), 1.89 (d, J=8.08 Hz, 2 H),1.67-1.56 (m, 1 H), 1.51-1.41 (m, 2 H), 1.32-1.17 (m, 1 H).

Example 3-16N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-cyclohexane-1,3-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andcyclohexane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 451, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.04 (d, J=7.8 Hz, 1 H), 7.57 (d, J=7.3 Hz, 1 H), 7.53-7.47(m, 2 H), 7.37 (t, J=7.7 Hz, 1 H), 7.32-7.26 (m, 2 H), 5.86 (s, 1 H),5.16-5.00 (m, 2 H), 3.65-3.50 (brs, 4 H), 3.16 (brs, 1 H), 2.42 (s, 3H), 2.45-2.38 (m, 1 H), 2.29 (d, J=11.1 Hz, 1 H), 2.03-1.85 (m, 3 H),1.54-1.42 (m, 1 H), 1.40-1.24 (m, 3 H).

Example 3-17(R)-1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4-dimethyl-pyrrolidin-3-ol

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(3R)-4,4-dimethylpyrrolidin-3-ol. MS obsd. (ESI⁺) [(M+H)⁺] 452, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.94 (dd, J=7.83, 1.01 Hz, 1 H), 7.83-7.73 (m, 2H), 7.58 (td, J=7.58, 1.26 Hz, 1 H), 7.47-7.37 (m, 2 H), 7.23 (dd,J=8.59, 1.77 Hz, 1 H), 6.03 (s, 1 H), 5.11 (s, 2 H), 4.02 (dd, J=10.36,5.31 Hz, 1 H), 3.93 (dd, J=5.05, 3.79 Hz, 1 H), 3.61-3.47 (m, 4 H), 2.37(s, 3 H), 1.15 (s, 3 H), 1.10-1.05 (m, 3 H).

Example 3-18cis-N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-cyclohexane-1,4-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andcis-cyclohexane-1,4-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 451, ¹H NMR (400MHz, DMSO-d6) δ ppm 7.91-7.85 (m, 2 H), 7.79 (s, 1 H), 7.58 (td, J=7.45,1.26 Hz, 1 H), 7.51-7.44 (m, 1 H), 7.29 (d, J=8.59 Hz, 1 H), 7.21 (dd,J=8.59, 1.52 Hz, 1 H), 6.17 (d, J=7.58 Hz, 1 H), 6.03 (s, 1 H), 5.06(brs, 2 H), 4.50 (brs, 1 H), 4.11 (d, J=4.55 Hz, 1 H), 3.67 (d, J=4.80Hz, 1 H), 3.64-3.56 (m, 2 H), 3.16 (m, 2 H), 3.06 (brs, 1 H), 2.35 (s, 3H), 1.83-1.44 (m, 8 H).

Example 3-19N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2-difluoropropane-1,3-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2,2-difluoropropane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 447, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.09-8.07 (d, 1 H), 7.95 (s, 1 H), 7.86-7.84 (d,1 H), 7.77-7.69 (m, 2 H), 7.64-7.58 (m, 2 H), 6.26 (s, 1 H), 5.34 (s, 2H), 4.53 (s, 2 H), 4.23 (t, 2 H), 3.74-3.66 (m, 4 H), 2.48 (s, 3 H).

Example 3-20N-[6-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2,2-difluoropropane-1,3-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4,6-trichloroquinoline) and2,2-difluoropropane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 467, ¹H NMR(400 MHz, DMSO-d6) δ ppm 8.17-8.08 (m, 1 H), 7.94 (d, J=7.07 Hz, 1 H),7.88 (dd, J=7.83, 1.26 Hz, 1 H), 7.62 (td, J=7.45, 1.26 Hz, 1 H),7.54-7.39 (m, 3 H), 7.14 (brs, 1 H), 6.33 (s, 1 H), 5.77 (s, 1 H), 5.11(brs, 2 H), 4.43 (brs, 2 H), 4.03-3.87 (m, 2 H), 3.61 (brs, 2 H),3.13-3.29 (m, 2 H).

Example 3-21N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-fluoropropane-1,3-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2-fluoropropane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 429, ¹H NMR (400MHz, CD₃OD) δ ppm 7.98 (dd, J=7.83, 1.01 Hz, 1 H), 7.84 (d, J=7.58 Hz, 1H), 7.65-7.57 (m, 2 H), 7.47-7.38 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1H), 6.10 (s, 1 H), 5.14 (s, 2 H), 4.69 (s, 2 H), 3.64 (d, J=5.31 Hz, 1H), 3.61-3.52 (m, 4 H), 3.04-2.91 (m, 2 H), 2.41 (s, 3 H).

Example 3-22N-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4,6-trichloroquinoline) and3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 459, ¹H NMR (400MHz, CD₃OD) δ ppm 8.34 (s, 1 H), 8.02-8.00 (t, J=4.0, 2.4 Hz, 2 H),7.92-7.90 (d, J=7.2 Hz, 1 H), 7.65-7.62 (m, 1 H), 7.56-7.54 (d, J=9.2Hz, 1 H), 7.49-7.44 (m, 2 H), 6.27 (s, 1 H), 5.22 (s, 2 H), 4.67-4.63(m, 4 H), 4.56 (s, 1 H), 3.78 (s, 2 H), 3.63-3.60 (t, J=4.8 Hz, 2 H).

Example 3-23[4-{[(3-Aminooxetan-3-yl)methyl]amino}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol

Methyl4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate

To a cooled solution of methyl4-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate(2.0 g, 5.2 mmol, prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepinein Example 1-1 by using methyl 2,4-dichoroquinoline-6-carboxylate and2,3,4,5-tetrahydro-1,4-benzothiazepine) in dichloromethane (30 mL) wasadded 3-chloroperoxybenzoic acid (2.63 g, 20.8 mmol) in an ice-bath.After being stirred for 1 hour at 0° C., the reaction mixture was washedwith brine, dried over sodium sulfate and concentrated in vacuo toafford 2.0 g of the crude product.

4-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanol

To a solution of methyl4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate (2.0 g, 4.8 mmol) in tetrahydrofuran (50mL) was added sodium borohydride (729 mg, 19.2 mmol). After beingrefluxed for 60 hours, the reaction mixture was diluted with water (30mL) and extracted with dichloromethane (50 mL×2). The combined organiclayers were dried over sodium sulfate and concentrated in vacuo toafford 1.4 g of the crude product.

[4-{[(3-Aminooxetan-3-yl)methyl]amino}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanoland 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 455, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.33 (s, 1 H), 8.08-8.05 (d, J=11.2 Hz, 2 H),7.94-7.92 (d, J=7.2 Hz, 1 H), 7.74-7.68 (m, 3 H), 7.57-7.53 (t, J=7.6Hz, 1 H), 6.26 (s, 1 H), 5.31 (s, 2 H), 4.72 (s, 2 H), 44.57 (s, 4 H),4.44 (s, 1 H), 3.88 (s, 2 H), 3.77-3.71 (m, 2 H).

Example 3-24N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-fluoro-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-7-fluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,4-dichloro-7-fluoro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 457, ¹H NMR (400MHz, CD₃OD) δ ppm 8.05-8.03 (d, J=8.0 Hz, 1 H), 7.92-7.88 (t, J=8.8, 8.0Hz, 2 H), 7.68-7.65 (m, 1 H), 7.53-7.49 (t, J=7.6 Hz, 1 H), 7.28-7.25(d, J=11.6 Hz, 1 H), 6.20 (s, 1 H), 5.24 (s, 2 H), 4.66-4.48 (m, 6 H),3.82 (s, 2 H), 3.66-3.64 (m, 2 H), 2.68 (s, 3 H).

Example 3-25N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-5-fluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,4-dichloro-5-fluoro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 457, ¹H NMR (400MHz, DMSO-d6) δ ppm 7.99-7.97 (d, J=7.2 Hz, 1 H), 7.90-7.88 (m, 1 H),7.66-7.62 (m, 1 H), 7.51-7.47 (t, J=7.6 Hz, 1 H), 7.29-7.24 (t, J=8.8,8.4 Hz, 1 H), 7.20-7.18 (d, J=8.4 Hz, 1 H), 6.61-6.57 (d, J=16.0 Hz, 1H), 6.12 (s, 1 H), 5.11 (s, 2 H), 4.44-4.43 (d, J=6.0 Hz, 2 H),4.38-4.37 (d, J=6.0 Hz, 2 H), 3.63-3.61 (t, J=4.8, 4.4 Hz, 2 H), 3.53(s, 2 H), 2.68-2.67 (t, J=2.0, 1.6 Hz, 1 H), 2.34-2.33 (t, J=2.0, 1.6, 1H), 1.92 (s, 3 H).

Example 3-26N^(˜)1^(˜)-[6-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2-methylpropane-1,2-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4,6-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and 2-methylpropane-1,2-diamine.MS obsd. (ESI⁺) [(M+H)⁺] 445, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (d,J=8.0 Hz, 2 H), 7.87 (d, J=7.2 Hz, 1 H), 7.61 (t, J=7.2 Hz, 1 H),7.49-7.43 (m, 2 H), 7.38 (dd, J=2.0, 8.8 Hz, 1 H), 6.13 (s, 1 H), 5.16(s, 2 H), 4.54 (brs, 2 H), 3.57 (t, J=4.4 Hz, 2 H), 3.27 (s, 2 H), 1.26(s, 6 H).

Example 3-272-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(tetrahydro-2H-pyran-4-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andtetrahydro-2H-pyran-4-ylamine. MS obsd. (ESI⁺) [(M+H)⁺] 438, ¹H NMR (400MHz, DMSO-d6) δ ppm 7.89 (dd, J=6.95, 3.41 Hz, 2 H), 7.78 (s, 1 H), 7.59(t, J=7.07 Hz, 1 H), 7.47 (t, J=7.58 Hz, 1 H), 7.31 (d, J=8.59 Hz, 1 H),7.23 (d, J=8.59 Hz, 1 H), 6.33 (d, J=8.08 Hz, 1 H), 6.09 (s, 1 H), 5.09(brs, 2 H), 4.44 (brs, 1 H), 3.99 (d, J=9.85 Hz, 2 H), 3.94-3.82 (m, 1H), 3.69-3.52 (m, 4 H), 2.36 (s, 3 H), 1.85 (d, J=11.87 Hz, 2 H),1.69-1.44 (m, 2 H).

Example 3-282-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(piperazin-1-yl)ethyl]quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2-(piperazin-1-yl)ethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 466, ¹H NMR (400MHz, DMSO-d6) ppm 7.925 (d, J=8.0 Hz, 1 H), 7.806 (d, J=7.2 Hz, 1 H),7.516-7.575 (m, 2 H), 7.359-7.395 (m, 2 H), 7.238 (m, 1 H), 5.98 (s, 1H), 5.10 (s, 2 H), 4.49 (brs, 2 H), 3.538 (m, 2 H), 3.542 (m, 2 H), 3.44(t, J=6.57 Hz, 2 H), 3.32 (s, 2 H), 2.89 (t, J=4.80 Hz, 4 H), 2.71 (t,J=6.57 Hz, 2 H), 2.56 (brs, 4 H), 2.37 (s, 3 H).

Example 3-292-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-4-ylmethyl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and1-(piperidin-4-yl)methanamine. MS obsd. (ESI⁺) [(M+H)⁺] 451, ¹H NMR (400MHz, DMSO-d6) δ ppm 9.89 (brs, 2 H), 7.875 (t, J=8.0 Hz, 2 H), 7.76 (s,1 H), 7.625 (t, J=6.8 Hz, 1 H), 7.48 (d, J=7.6 Hz, 1 H), 7.30 (d, J=8.4Hz, 1 H), 7.226 (d, J=1.6 Hz, 1 H), 6.73 (t, J=5.43 Hz, 1 H), 5.07 (brs,2 H), 4.42 (brs, 2 H), 4.10 (d, J=12.63 Hz, 2 H), 3.63 (m, 2 H),3.23-3.05 (m, 2 H), 2.50 (s, 2 H), 2.05 (s, 3 H), 1.76-1.66 (m, 3 H),1.15-0.98 (m, 2 H).

Example 3-30N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]heptane-1,7-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andheptane-1,7-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 467, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.07 (dd, J=1.2, 0.8 Hz, 1 H), 7.97 (s, 1 H), 7.92 (d,J=7.6 Hz, 1 H), 7.74-7.68 (m, 2 H), 7.61-7.56 (m, 2 H), 5.91 (s, 1 H),5.32 (s, 2 H), 4.52 (brs, 2 H), 3.75 (d, J=4.80 Hz, 2 H), 3.31 (d,J=1.60 Hz, 2 H), 2.94 (m, 2 H), 2.45 (s, 3 H), 1.72 (m, 4 H), 1.50 (m, 6H).

Example 3-31N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-methylethane-1,2-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andN-methylethane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400MHz, CD₃OD) δ ppm 8.03-8.0 (m, 3 H), 7.87-7.84 (d, J=8.8 Hz, 1 H),7.71-7.70 (d, J=1.2 Hz, 1 H), 7.57-7.53 (m, 2 H), 6.07 (s, 1 H), 5.40(s, 2 H), 4.56 (s, 2 H), 3.96-3.93 (dd, J=6.0, 6.4 Hz, 2 H), 3.75-3.73(q, J=4.4 Hz, 2 H), 3.43-3.40 (q, J=6 Hz, 2 H), 2.80 (s, 3 H), 2.46 (s,3 H).

Example 3-32N′-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N,N-dimethylethane-1,2-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andN,N-dimethylethane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 425, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.05-8.01 (m, 3 H), 7.88-7.86 (d, J=8.8 Hz, 1 H),7.70-7.68 (d, J=1.2 Hz, 1 H), 7.56-7.52 (m, 2 H), 6.05 (s, 1 H), 5.41(s, 2 H), 4.56 (s, 2 H), 3.96-3.93 (dd, J=6.0, 6.4 Hz, 2 H), 3.75-3.73(q, J=4.4 Hz, 2 H), 3.43-3.40 (q, J=6.0 Hz, 2 H), 3.01 (s, 3 H), 2.45(s, 3 H).

Example 3-332-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N,6-dimethylquinolin-4-aminetrifluoroacetate

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andmethylamine. MS obsd. (ESI⁺) [(M+H)⁺] 368, ¹H NMR (400 MHz, DMSO-d6) δppm 11.47 (s, 1 H), 8.45 (brs, 1 H), 7.99 (m, 3 H), 7.75 (m, 2 H), 7.60(m, 2 H), 5.92 (s, 1 H), 5.33 (s, 2 H), 4.48 (s, 2 H), 3.91 (s, 2 H),3.02 (s, 3 H), 2.33 (s, 3 H).

Example 3-34(3S,4S)-1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3,4-diol

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(3S,4S)-pyrrolidine-3,4-diol. MS obsd. (ESI⁺) [(M+H)⁺] 440, ¹H NMR (400MHz, CD₃OD) δ ppm 8.03 (s, 1 H), 8.01 (s, 1 H), 7.80-7.78 (d, J=7.6 Hz,1 H), 7.67-7.63 (m, 2 H), 7.54-7.50 (m, 2 H), 5.83 (s, 1 H), 5.21 (s, 2H), 4.45 (s, 2 H), 4.22 (s, 2 H), 4.18-4.15 (m, 2 H), 3.67-3.60 (m, 4H), 2.41 (s, 3 H).

Example 3-352-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-2-ylmethyl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and1-(pyrrolidin-2-yl)methanamine. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.96-7.94 (m, 2 H), 7.90 (d, J=7.6 Hz, 1 H), 7.70(d, J=8.4 Hz, 1 H), 7.61 (t, J=7.6 Hz, 1 H), 7.47-7.45 (m, 2 H), 6.01(s, 1 H), 5.33-5.25 (m, 2 H), 4.55-4.41 (m, 2 H), 3.96-3.73 (m, 3 H),3.64 (s, 2 H), 3.38-3.31 (m, 1 H), 3.29-3.27 (m, 1 H), 2.37 (s, 3 H),2.28-2.21 (m, 1 H), 2.13-1.96 (m, 2 H), 1.89-1.81 (m, 1 H).

Example 3-364-[4-(1,4-Diazepan-1-yl)-6-methylquinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

The title compound was prepared in analogy to Example 3-1 1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and1,4-diazepine. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR (400 MHz, CD₃OD) δppm 7.99 (d, J=7.2 Hz, 1 H), 7.86 (d, J=7.2 Hz, 1 H), 7.81 (d, J=8.8 Hz,1 H), 7.72-7.68 (m, 2 H), 7.58-7.51 (m, 2 H), 6.31 (s, 1 H), 5.32 (s, 2H), 4.54 (s, 2 H), 4.06-4.04 (m, 2 H), 3.90-3.87 (m, 2 H), 3.72 (s, 2H), 3.63-3.61 (m, 2 H), 3.46-3.42 (m, 2 H), 2.45 (s, 3 H), 2.32 (s, 2H).

Example 3-37N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-ethylethane-1,2-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andN-ethylethane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 425, ¹H NMR (400MHz, CD₃OD) δ ppm 8.05 (d, J=7.2 Hz, 1 H), 7.99-7.97 (m, 2 H), 7.81 (d,J=8.4 Hz, 1 H), 7.67 (t, J=7.2 Hz, 1 H), 7.51-7.46 (m, 2 H), 6.08 (s, 1H), 5.37 (s, 2 H), 4.57 (s, 2 H), 3.91 (t, J=6.4 Hz, 2 H), 3.69 (t,J=4.8 Hz, 2 H), 3.37 (t, J=6.4 Hz, 2 H), 3.15 (q, J=7.2 Hz, 2 H), 2.43(s, 3 H), 1.35 (t, J=7.2 Hz, 3 H).

Example 3-382-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}ethanol

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2-aminoethanol. MS obsd. (ESI⁺) [(M+H)⁺] 398, ¹H NMR (400 MHz, CD₃OD) δppm 8.08 (d, J=7.6 Hz, 1 H), 7.91 (s, 1 H), 7.85 (d, J=7.6 Hz, 1 H),7.74-7.67 (m, 2 H), 7.59-7.56 (m, 2 H), 6.09 (s, 1 H), 5.29 (s, 2 H),4.51 (s, 2 H), 3.83 (t, J=5.6 Hz, 2 H), 3.74-3.72 (m, 2 H), 3.62 (t,J=5.6 Hz, 2 H), 2.47 (s, 3 H).

Example 3-392-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-4-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andpiperidin-4-amine. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR (400 MHz, CD₃OD)δ ppm 8.05 (t, J=8 Hz, 2 H), 7.88 (d, J=8 Hz, 1 H), 7.73-7.69 (m, 2 H),7.59-7.57 (m, 2 H), 6.04 (s, 1 H), 5.33 (s, 2 H), 4.52 (s, 2 H),4.18-4.11 (m, 1 H), 3.74 (s, 2 H), 3.61-3.57 (m, 2 H), 3.33-3.26 (m, 2H), 2.46 (s, 3 H), 2.24-2.19 (m, 2 H), 2.01-1.91 (m, 2 H).

Example 3-402-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-3-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andpiperidin-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR (400 MHz, CD₃OD)δ ppm 8.09-8.07 (d, J=8 Hz, 1 H), 7.99 (s, 1 H), 7.89-7.87 (q, J=7.2 Hz,1 H), 7.73-7.68 (q, J=14 Hz, 2 H), 7.62-7.55 (m, 2 H), 6.14 (s, 1 H),5.36 (s, 2 H), 4.58-4.51 (m, 2 H), 4.34 (s, 1 H), 3.75 (s, 2 H),3.63-3.60 (d, J=11.6 Hz, 1 H), 3.47-3.44 (m, 1 H), 3.07-3.02 (d, J=11.6Hz, 2 H), 2.47 (s, 3 H), 2.17-2.14 (m, 2 H), 2.05-2.00 (m, 1 H),1.85-1.84 (m, 1 H).

Example 3-412-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-2-ylmethyl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and1-(piperidin-2-yl)methanamine. MS obsd. (ESI⁺) [(M+H)⁺] 451, ¹H NMR (400MHz, CD₃OD) δ ppm 8.07 (d, J=7.6 Hz, 1 H), 7.93 (s, 1 H), 7.85 (d, J=7.6Hz, 1 H), 7.73-7.70 (m, 2 H), 7.62-7.58 (m, 2 H), 6.02 (s, 1 H), 5.35(s, 2 H), 4.51 (s, 2 H), 3.75-3.71 (m, 4 H), 3.51-3.40 (m, 2 H),2.98-2.92 (m, 1 H), 2.46 (s, 3 H), 2.11-2.05 (m, 1 H), 1.96-1.90 (m, 2H), 1.78-1.56 (m, 3 H).

Example 3-422-[(2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}ethyl)amino]ethanol

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2-[(2-aminoethyl)amino]ethanol. MS obsd. (ESI⁺) [(M+H)⁺] 441, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.94 (d, J=7.6 Hz, 1 H), 7.81 (d, J=6.8 Hz, 1 H),7.61-7.57 (m, 2 H), 7.43-7.38 (m, 2 H), 7.24 (d, J=7.6 Hz, 1 H), 6.02(s, 1 H), 5.12 (s, 2 H), 4.51 (brs, 2 H), 3.69 (t, J=5.2 Hz, 2 H),3.55-3.52 (m, 2 H), 3.49 (t, J=6.0 Hz, 2 H), 3.01 (t, J=6.0 Hz, 2 H),2.83 (t, J=5.6 Hz, 2 H), 2.38 (s, 3 H).

Example 3-43N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2,3,3-tetrafluorobutane-1,4-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2,2,3,3-tetrafluorobutane-1,4-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 497, ¹HNMR (400 MHz, CD₃OD) δ ppm 7.99 (d, J=6.8 Hz, 1 H), 7.78 (d, J=6.4 Hz, 1H), 7.58-7.62 (m, 2 H), 7.43-7.47 (m, 2 H), 7.30-7.32 (m, 1 H), 6.19 (s,1 H), 5.13 (s, 2 H), 4.58 (brs, 2 H), 4.12 (t, J=16 Hz, 2 H), 3.58 (t,J=4.8 Hz 2 H), 3.34-3.20 (m, 2 H), 2.43 (s, 3 H).

Example 3-44N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(2-methoxyethyl)ethane-1,2-diamine

The title compound was prepared in analogy to Example 3-1 1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andN-(2-methoxyethyl)ethane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 455, ¹HNMR (400 MHz, CD₃OD) δ ppm 8.06-8.04 (d, J=7.6 Hz, 1 H), 7.88-7.86 (m, 2H), 7.73-7.70 (m, 2 H), 7.59-7.56 (m, 2 H), 6.01 (s, 1 H), 5.33 (s, 2H), 4.55 (s, 2 H), 3.88-3.78 (m, 2 H), 3.72 (s, 2 H), 3.67-3.65 (t,J=4.8 Hz, 2 H), 3.45-3.42 (t, J=6 Hz, 2 H), 3.38 (s, 3 H), 3.30-3.28 (m,2 H), 2.45 (s, 3 H).

Example 3-451-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-methylpyrrolidin-3-ol

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and3-methylpyrrolidin-3-ol. MS obsd. (ESI⁺) [(M+H)⁺] 438, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.06-8.01 (m, 2 H), 7.84-7.82 (d, J=7.2 Hz, 1 H), 7.74-7.68(m, 2 H), 7.57-7.53 (m, 2 H), 5.81 (s, 1 H), 5.26 (s, 2 H), 4.49 (s, 2H), 4.12-3.31 (m, 3 H), 3.27-3.21 (m, 3 H), 2.44 (s, 3 H), 2.08 (s, 2H), 1.50 (s, 3 H).

Example 3-46N-[6-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4,6-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd.(ESI⁺) [(M+H)⁺] 417, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.01-7.99 (d, J=8.8Hz, 1 H), 7.90 (s, 1 H), 7.86-7.84 (d, J=7.2 Hz, 1 H), 7.53-7.38 (m, 4H), 6.10 (s, 1 H), 5.18 (s, 2 H), 3.59-3.40 (m, 4 H), 3.19-3.10 (m, 2H).

Example 3-472-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(oxetan-3-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andoxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 410, ¹H NMR (400 MHz, CD₃OD) δppm 7.97 (d, J=1.9 Hz, 1 H), 7.79 (d, J=1.9 Hz, 1 H), 7.72 (s, 1 H),7.63 (t, J=3.8 Hz, 1 H), 7.44 (t, J=4.3 Hz, 2 H), 7.29 (d, J=2.1 Hz, 1H), 5.72 (s, 1 H), 5.16 (t, J=3.3 Hz, 2 H), 5.12 (s, 2 H), 4.86 (m, 1H), 4.72 (t, J=3.0 Hz, 2 H), 4.53 (brs, 2 H), 3.58 (t, J=2.3 Hz, 2 H),2.43 (s, 3 H).

Example 3-48N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4-dichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 425, ¹H NMR (400MHz, CD₃OD) δ ppm 7.96 (d, J=1.8 Hz, 1 H), 7.89 (m, J=5.5 Hz, 2 H), 7.63(m, J=4.0 Hz, 1 H), 7.44 (m, J=7.6 Hz, 3 H), 7.12-7.08 (m, J=4.1 Hz, 1H), 6.58 (d, J=0.8 Hz, 1 H), 6.22 (s, 1 H), 5.11 (s, 2 H), 4.48-4.39 (m,J=9.0 Hz, 6 H), 3.65-3.58 (m, J=6.1 Hz, 4 H).

Example 3-492-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[(3R)-tetrahydrofuran-3-yl]quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(3R)-tetrahydrofuran-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 424, ¹H NMR (400MHz, CD₃OD) δ ppm 7.89 (t, J=4.4 Hz, 2 H), 7.83 (s, 1 H), 7.65 (t, J=3.7Hz, 1 H), 7.47 (t, J=3.8 Hz, 1 H), 7.31 (d, J=2.1 Hz, 1 H), 7.24 (d,J=2.1 Hz, 1 H), 6.56 (d, J=1.5 Hz, 1 H), 6.01 (s, 1 H), 5.08 (s, 2 H),4.40 (brs, 2 H), 4.02 (t, J=3.6 Hz, 1 H), 3.88 (m, J=7.2 Hz, 1 H), 3.80(m, J=5.4 Hz, 1 H), 3.64 (d, J=4.5 Hz, 3 H), 2.30 (t, J=3.7 Hz, 4 H).

Example 3-50N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andoxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 453, ¹H NMR (400MHz, CD₃OD) δ ppm 8.04 (d, J=1.8 Hz, 1 H), 7.90 (d, J=1.9 Hz, 1 H), 7.81(s, 1 H), 7.67 (t, J=3.6 Hz, 1 H), 7.57 (d, J=2.1 Hz, 1 H), 7.52 (t,J=3.8 Hz, 1 H), 7.43 (d, J=2.1 Hz, 1 H), 6.21 (s, 1 H), 5.26 (s, 2 H),4.63 (s, 4 H), 4.55 (brs, 2 H), 3.82 (s, 2 H), 3.67 (t, J=2.4 Hz, 2 H),3.45 (brs, 2 H), 2.46 (s, 3 H).

Example 3-51N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4,6-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) andoxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 473, ¹H NMR (400MHz, CD₃OD) δ ppm 8.00 (m, J=2.2 Hz, 1 H), 7.89 (t, J=2.9 Hz, 2 H), 7.63(m, J=4.1, 1 H), 7.45 (m, J=6.5 Hz, 2 H), 7.37 (m, J=2.8 Hz, 1 H), 6.21(d, 1 H), 5.18 (s, 2 H), 4.56 (m, J=4.6 Hz, 6 H), 3.67 (s, 2 H), 3.58(t, J=2.4 Hz, 2 H), 3.15 (s, 2 H).

Example 3-52N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4-dichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) andoxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 439, ¹H NMR (400MHz, CD₃OD) δ ppm 8.32 (d, J=2.1 Hz, 1 H), 8.11 (t, J=2.0 Hz, 1 H), 8.04(d, J=1.9 Hz, 1 H), 7.93 (d, J=2.0 Hz, 1 H), 7.77 (m, J=8.3 Hz, 2 H),7.63 (t, J=3.7 Hz, 1 H), 7.53 (d, J=3.8 Hz, 1 H), 6.30 (s, 1 H), 5.45(s, 2 H), 4.65 (m, J=5.5 Hz, 6 H), 4.01 (s, 2 H), 3.83 (t, J=2.4 Hz, 2H), 3.51 (s, 2 H).

Example 3-532-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(oxetan-3-ylmethyl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and1-(oxetan-3-yl)methanamine. MS obsd. (ESI⁺) [(M+H)⁺] 424, ¹H NMR (400MHz, DMSO-d6) δ ppm 7.93 (d, 1 H), 7.89-7.87 (t, 1 H), 7.69-7.65 (m, 2H), 7.50-7.46 (t, 1 H), 7.31 (d, 1 H), 7.24-7.21 (m, 1 H), 6.79-6.76 (t,1 H), 6.04 (s, 1 H), 5.08 (s, 2 H), 4.74-4.70 (m, 2 H), 4.37 (t, 4 H),3.61 (t, 4 H), 3.28 (m, 1 H), 2.35 (s, 3 H)

Example 3-54N-[(1-Aminocyclobutyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and1-(aminomethyl)cyclobutanamine. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.97 (m, J=2.0 Hz, 1 H), 7.86 (d, J=1.8 Hz, 1 H),7.70 (s, 1 H), 7.61 (t, J=3.6 Hz, 1 H), 7.45 (m, J=3.0 Hz, 2 H), 7.30(m, J=2.5 Hz, 1 H), 6.13 (s, 1 H), 5.18 (s, 2 H), 4.53 (br. s., 2 H),3.59 (t, J=2.3 Hz, 2 H), 3.46 (s, 2 H), 2.43 (s, 3 H), 2.28-2.22 (m,J=6.3 Hz, 2 H), 2.12-2.03 (m, J=9.2 Hz, 2 H), 1.97-1.82 (m, J=14.7 Hz, 2H).

Example 3-55N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pentane-1,5-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andpentane-1,5-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 439, ¹H NMR (400 MHz,CDCl₃) δ ppm 7.96 (d, J=7.6 Hz, 1 H), 7.54 (d, J=6.8 Hz 1 H), 7.42 (m, 2H), 7.30 (d, J=6.4 Hz, 1 H), 7.21 (m, 2 H), 5.81 (s, 1 H), 5.03 (s, 2H), 4.61 (m, 2 H), 3.49 (brs, 2 H), 3.19 (m, 2 H), 2.71 (d, J=6.40 Hz, 2H), 2.94 (m, 2 H), 2.34 (s, 3 H), 1.61 (s, 2 H), 1.49 (m, 4 H).

Example 3-56N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]hexane-1,6-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andhexane-1,6-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 453, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.07 (dd, J=1.2, 0.8 Hz, 1 H), 7.97 (s, 1 H), 7.92 (d,J=7.6 Hz, 1 H), 7.80 (d, J=8.8 Hz, 1 H), 7.70 (d, J=1.2 Hz, 1 H), 7.57(dd, J=7.20, 1.6 Hz, 2 H), 5.91 (s, 1 H), 5.32 (s, 2 H), 4.52 (brs, 2H), 3.75 (d, J=4.80 Hz, 2 H), 3.31 (d, J=1.60 Hz, 2 H), 2.94 (m, 2 H),2.45 (s, 3 H), 1.72 (m, 4 H), 1.50 (m, 4 H).

Example 3-57N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-1,1,1-trifluoromethanesulfonamidehydrochloride

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and1,1,1-trifluoromethanesulfonamide. MS obsd. (ESI⁺) [(M+H)⁺] 486, ¹H NMR(400 MHz, DMSO-d6) δ ppm 7.99-7.92 (m, 2 H), 7.85-7.80 (d, J=7.2 Hz, 1H), 7.78-7.73 (d, J=2 Hz, 1 H), 7.72-7.65 (t, J=7.6 Hz, 1 H), 7.62-7.51(m, 2 H), 7.13 (s, 1 H), 5.07 (s, 2 H), 4.60-4.40 (m, 2 H), 3.98-3.91(t, J=2.8 Hz, 2 H), 2.39 (s, 3 H).

Example 3-58N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyridazine-3-carboxamide

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andpyridazine-3-carboxamide. MS obsd. (ESI⁺) [(M+H)⁺] 460, ¹H NMR (400 MHz,CD₃OD) δ ppm 9.52-9.48 (d, J=8 Hz, 1 H), 8.68 (s, 1 H), 8.62-8.58 (d,J=7.6 Hz, 1 H), 8.10-8.02 (m, 3 H), 7.94 (s, 1 H), 7.88-7.82 (d, J=8 Hz,1 H), 7.75-7.68 (t, J=7.6 Hz, 2 H), 7.60-7.52 (t, J=7.2 Hz, 1 H), 5.36(s, 2 H), 4.80-4.55 (m, 2 H), 3.83-3.78 (t, J=2.8 Hz, 2 H), 2.56 (s, 3H).

Example 3-59N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]benzamide

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andbenzamide. MS obsd. (ESI⁺) [(M+H)⁺] 458, ¹H NMR (400 MHz, CD₃OD) δ ppm8.64 (s, 1 H), 8.09-8.04 (m, 5 H), 7.89-7.87 (d, J=8.4 Hz, 1 H),7.75-7.67 (m, 3 H), 7.62-7.55 (m, 3 H), 5.34 (s, 2 H), 4.62 (s, 2 H),3.76 (s, 2 H), 2.53 (s, 3 H).

Example 3-60N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]acetamide

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andacetamide. MS obsd. (ESI⁺) [(M+H)⁺] 396, ¹H NMR (400 MHz, CD₃OD) δ ppm8.53 (s, 1 H), 8.10-8.06 (m, 2 H), 7.97-7.85 (d, J=8.4 Hz, 1 H),7.82-7.80 (d, J=9.2 Hz, 1 H), 7.76-7.72 (m, 2 H), 7.58-7.54 (m, 2 H),5.28 (s, 2 H), 4.60 (s, 2 H), 3.77-3.71 (m, 2 H), 2.52 (s, 3 H), 2.40(s, 3 H).

Example 3-61N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-3-carboxamide

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 4,6-dibromoquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and piperidine-3-carboxamide. MSobsd. (ESI⁺) [(M+H)⁺] 465, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.47 (s, 1 H),8.11 (s, 1 H), 8.07-8.05 (d, J=1.2 Hz, 1 H), 7.98-7.96 (d, J=7.2 Hz, 1H), 7.83-7.80 (d, J=8.4 Hz, 1 H), 7.70-7.64 (m, 2 H), 7.58-7.54 (m, 1H), 5.29 (s, 1 H), 4.61 (s, 2 H), 3.76 (s, 2 H), 3.55-3.52 (m, 2 H),3.43-3.34 (m, 3 H), 3.22-3.15 (m, 1 H), 2.52 (s, 3 H), 2.29-2.27 (m, 1H), 2.06-2.02 (m, 1 H), 1.97-1.89 (m, 2 H).

Example 3-62N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-4-carboxamide

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andpiperidine-4-carboxamide. MS obsd. (ESI⁺) [(M+H)⁺] 465, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.50 (s, 1 H), 8.14 (s, 1 H), 8.01-7.98 (d, J=1.2 Hz, 1 H),7.95-7.93 (d, J=7.2 Hz, 1 H), 7.84-7.82 (d, J=8.8 Hz, 1 H), 7.66-7.61(m, 2 H), 7.52-7.51 (m, 1 H), 5.23 (s, 1 H), 4.59 (s, 2 H), 3.74 (s, 2H), 3.57-3.54 (m, 2 H), 3.22-3.10 (m, 4 H), 2.50 (s, 3 H), 2.26-2.22 (m,2 H), 2.14-2.08 (m, 2 H).

Example 3-633-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-1,1-dimethylurea

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and1,1-dimethylurea. MS obsd. (ESI⁺) [(M+H)⁺] 425, ¹H NMR (400 MHz, CD₃OD)δ ppm 7.83 (d, J=7.6 Hz, 1 H), 7.68 (t, J=3.6 Hz, 2 H), 7.42 (q, J=7.2Hz, 2 H), 7.23-7.20 (m, 2 H), 7.15 (s, 1 H), 5.00 (s, 2 H), 4.45 (brs, 2H), 3.42 (s, 2 H), 3.02 (s, 6 H), 2.30 (s, 3 H).

Example 3-642-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(1,2-oxazol-3-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 4,6-dibromoquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and 1,2-oxazol-3-amine. MS obsd.(ESI⁺) [(M+H)⁺] 421, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.72 (s, 1 H), 8.20(s, 2 H), 8.14 (d, J=7.2 Hz, 1 H), 8.07 (d, J=7.6 Hz, 1 H), 7.83 (d,J=8.8 Hz, 1 H), 7.63-7.68 (m, 2 H), 7.56 (t, J=7.6 Hz, 1 H), 6.65 (s, 1H), 5.29 (s, 2 H), 4.61 (s, 2 H), 3.79 (s, 2 H), 2.54 (s, 3 H).

Example 3-65N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-trideuteriomethylquinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-trideuteriomethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,4-dichloro-6-trideuteriomethylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) andoxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 456, ¹H NMR (400MHz, CDCl₃) δ ppm 8.04 (d, 1 H), 7.68 (d, 1 H), 7.51 (m, 2 H), 7.36 (t,1 H), 7.29 (s, 1 H), 7.22 (d, 1 H), 7.08 (s, 1 H), 5.92 (s, 1 H), 5.13(s, 2 H), 4.57 (s, 6 H), 3.67 (s, 2 H), 3.57 (s, 2 H), 3.34 (s, 2 H).

Example 4-1N-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine(prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepinein Example 1-1) and 3-aminomethyl-oxetan-3-ylamine. MS obsd. (ESI⁺)[(M+H)⁺] 410, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.94 (s, 1 H), 7.93-7.70 (m,1 H), 7.50-7.48 (d, J=8.4 Hz, 2 H), 7.40-7.37 (m, 1 H), 7.26-7.22 (m, 1H), 7.15-7.11 (m, 1 H), 6.20 (s, 1 H), 4.99 (s, 2 H), 4.63-4.61 (d,J=6.8 Hz, 2 H), 4.58-4.57 (d, J=6.4 Hz, 2 H), 4.38 (s, 2 H), 3.65 (s, 2H), 2.99-2.97 (t, J=4.8 Hz, 2 H).

Example 4-2N-[6-Chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 4-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine(prepared in analogy to the one in Example 4-1) and ethane-1,2-diamine.MS obsd. (ESI⁺) [(M+H)⁺] 385, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.901 (s, 1H), 7.70-7.60 (m, 1 H), 7.55-7.42 (m, 2 H), 7.378-3.350 (dd, J=8.8, 2.4Hz, 1 H), 7.28-7.16 (m, 1 H), 7.14-7.12 (m, 1 H), 6.05 (s, 1 H), 5.51(s, 1 H), 4.97 (s, 2 H), 4.38 (s, 2 H), 3.43-3.39 (t, J=6.4 Hz, 2 H),2.99-2.95 (m, 4 H).

Example 4-3N-[(3-Aminooxetan-3-yl)methyl]-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 4-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine(prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepinein Example 1-1) and 3-aminomethyl-oxetan-3-ylamine. MS obsd. (ESI⁺)[(M+H)⁺] 407, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.97 (s, 1 H), 7.74-7.67 (t,2 H), 7.61 (d, J=8.4 Hz, 1 H), 7.55 (d, J=7.6 Hz, 1 H), 7.32 (t, 1 H),7.26 (t, 1 H), 6.27 (s, 1 H), 5.19 (s, 2 H), 4.77-4.70 (m, 4 H), 4.35(s, 2 H), 4.12 (s, 2 H), 3.16 (t, J=9.6 Hz, 2 H), 2.49 (s, 3 H).

Example 4-41-[2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine

The title compound was prepared in analogy to Example 4-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine(prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepinein Example 1-1) and pyrrolidin-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 391, ¹HNMR (400 MHz, CD₃OD) δ ppm 8.07 (s, 1 H), 7.79 (d, J=8.4 Hz, 1 H),7.67-7.57 (m, 3 H), 7.38-7.30 (m, 2 H), 5.96 (s, 1 H), 5.17 (s, 2 H),4.45-4.35 (m, 2 H), 4.30-4.25 (m, 1 H), 4.20-4.11 (m, 2 H), 4.05-3.91(m, 2 H), 3.23 (t, J=4.8 Hz, 2 H), 2.51-2.50 (m, 1 H), 2.53 (s, 3 H),2.40-2.30 (m, 1 H).

Example 5-12-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-[2-(1,1-dioxidothiomorpholin-4-yl)ethyl]-6-methylquinolin-4-amine

To a solution of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (150 mg, 0.40 mmol, prepared in analogy to the one inExample 2-1) in 1,4-dioxane (4 mL) was added tris(dibenzylideneacetone)dipalladium (0) (40 mg, 0.04 mmol), 1,1′-bis(diphenyphosphino)ferrocene(25 mg, 0.04 mmol), sodium tert-butoxide (77 mg, 0.80 mmol) and2-(1,1-dioxidothio-morpholin-4-yl)ethanamine (107 mg, 0.60 mmol). Theresulting mixture was evacuated and refilled with nitrogen, sealed andheated at 120° C. overnight. After being cooled to room temperature, themixture was filtered and washed with ethyl acetate, the organic layerswere combined and concentrated in vacuo, the residue was purified byflash chromatography (eluenting with 2% methanol in dichloromethane) toafford 67 mg of the title compound as a light solid (yield was 40%). MSobsd. (ESI⁺) [(M+H)⁺] 515, ¹H NMR (400 MHz, CDCl₃) 8.05 (d, J=7.6 Hz, 1H), 7.66 (d, J=7.2 Hz, 1 H), 7.53-7.48 (m, 2 H), 7.37-7.28 (m, 2 H),7.21 (s, 1 H), 5.88 (s, 1 H), 5.26 (m, 1 H), 5.12 (s, 1 H), 4.6 (brs, 1H), 3.56 (m, 1 H), 3.33 (m, 2 H), 3.14 (m, 8 H), 2.99 (t, J=4.8 Hz, 2H), 2.46 (s, 3 H), 2.0 (d, J=4.5 Hz, 2 H).

Example 5-2N-[2-(2-Aminoethoxy)ethyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 5-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2,2′-oxydiethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 441, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.08 (dd, J=1.2, 7.6 Hz, 1 H), 7.92 (s, 1 H), 7.83 (d,J=7.2 Hz, 1 H), 7.70-7.67 (m, 2 H), 7.59-7.55 (m, 2 H), 5.96 (s, 1 H),5.28 (s, 2 H), 4.49 (s, 2 H), 3.81 (t, J=5.2 Hz, 2 H), 3.72-3.68 (m, 6H), 3.13 (t, J=4.8 Hz, 2 H), 2.45 (s, 3 H).

Example 5-3N˜1˜-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropane-1,2-diamine

The title compound was prepared in analogy to Example 5-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2-methylpropane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 425, ¹H NMR (400MHz, CD₃OD) δ ppm 7.97 (d, J=7.83 Hz, 1 H), 7.85 (d, J=7.58 Hz, 1 H),7.70 (s, 1 H), 7.60 (t, J=7.33 Hz, 1 H), 7.48-7.38 (m, 2 H), 7.29-7.27(m, 1 H), 6.09 (s, 1 H), 5.15 (brs, 2 H), 3.57 (brs, 2 H), 3.26 (s, 2H), 2.43 (s, 3 H), 1.34-1.20 (m, 6 H).

Example 5-4N˜1˜-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2-methylpropane-1,2-diamine

The title compound was prepared in analogy to Example 5-1 in Scheme 5 byusing 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using and 2,4-dichloroquinoline2,3,4,5-tetrahydro-1,4-benzothiazepine) and 2-methylpropane-1,2-diamine.MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.02-7.93(m, 1 H), 7.87 (s, 2 H), 7.64-7.57 (m, 1 H), 7.56-7.48 (m, 1 H), 7.42(s, 2 H), 7.19-7.09 (m, 1 H), 6.11 (s, 1 H), 5.23-5.07 (m, 2 H),3.63-3.51 (m, 2 H), 3.37 (s, 2 H), 3.33 (m, 2 H), 3.28 (s, 2 H), 1.26(s, 6 H).

Example 5-5N˜1˜-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,2-diamine

The title compound was prepared in analogy to Example 5-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andpropane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.91 (dd, J=7.83, 1.01 Hz, 1 H), 7.83 (d, J=7.33 Hz, 1 H),7.69 (s, 1 H), 7.58 (d, J=1.26 Hz, 1 H), 7.44 (d, J=8.59 Hz, 1 H),7.38-7.31 (m, 1 H), 7.28 (dd, J=8.59, 1.77 Hz, 1 H), 6.04 (s, 1 H), 5.13(brs, 2 H), 3.56 (t, J=4.67 Hz, 2 H), 3.52-3.41 (m, 4 H), 3.37 (s, 1 H),2.41 (s, 3 H), 1.38 (d, J=6.06 Hz, 3 H).

Example 5-64-[6-Methyl-4-(4-methylpiperazin-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

The title compound was prepared in analogy to Example 5-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and1-methylpiperazine. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.90 (dd, J=7.83, 1.01 Hz, 1 H), 7.79 (d, J=7.07 Hz, 1 H),7.60-7.45 (m, 3 H), 7.34 (td, J=7.64, 1.14 Hz, 1 H), 7.28 (dd, J=8.59,1.77 Hz, 1 H), 6.54 (s, 1 H), 5.11 (s, 2 H), 3.61-3.50 (m, 2 H), 3.37(s, 2 H), 3.17 (brs, 4 H), 2.80 (brs, 4 H), 2.46 (s, 3 H), 2.39 (s, 3H).

Example 5-71-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-2-ol

The title compound was prepared in analogy to Example 5-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 1-1) and1-aminopropan-2-ol. MS obsd. (ESI⁺) [(M+H)⁺] 412, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.99 (dd, J=7.71, 1.14 Hz, 1 H), 7.84 (d, J=7.07 Hz, 1 H),7.71 (s, 1 H), 7.64 (td, J=7.58, 1.26 Hz, 1 H), 7.55 (d, J=8.59 Hz, 1H), 7.50-7.41 (m, 1 H), 7.37 (dd, J=8.59, 1.52 Hz, 1 H), 6.03 (s, 1 H),5.16 (s, 2 H), 4.08 (dd, J=11.49, 6.44 Hz, 1 H), 3.62 (t, J=4.80 Hz, 2H), 3.44-3.35 (m, 4 H), 2.42 (s, 3 H), 1.33 (d, J=6.06 Hz, 3 H).

Example 5-8(2S)—N˜1˜-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,2-diamine

The title compound was prepared in analogy to Example 5-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(2S)-propane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.86 (d, J=7.58 Hz, 1 H), 7.71 (d, J=7.33 Hz, 1 H),7.67-7.60 (m, 1 H), 7.49 (t, J=7.33 Hz, 1 H), 7.42 (d, J=8.59 Hz, 1 H),7.28-7.19 (m, 2 H), 6.07-5.83 (m, 1 H), 5.02 (brs, 2 H), 3.62 (s, 1 H),3.56-3.46 (m, 2 H), 3.37 (s, 2 H), 3.28-3.11 (m, 4 H), 2.36 (s, 3 H),0.92-0.80 (m, 2 H).

Example 5-9(2R)—N˜1˜-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,2-diamine

The title compound was prepared in analogy to Example 5-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(2R)-propane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.97 (d, J=7.83 Hz, 1 H), 7.82 (d, J=7.58 Hz, 1 H),7.70-7.55 (m, 2 H), 7.46-7.37 (m, 2 H), 7.33-7.22 (m, 2 H), 6.10-5.99(m, 1 H), 5.13 (brs, 2 H), 3.65-3.52 (m, 3 H), 3.37 (m, 2 H), 3.31-3.20(m, 2 H), 2.41 (s, 3 H), 1.32-1.22 (m, 2 H).

Example 5-10N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7,8-difluoro-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 5-1 in Scheme 5 byusing4-(4-chloro-6-methyl-7,8-difluoroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using4-chloro-6-methyl-7,8-dichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 475, ¹H NMR (400MHz, DMSO-d6) δ ppm 8.04 (brs, 1 H), 7.88 (d, J=7.83 Hz, 1 H), 7.62 (t,J=6.82 Hz, 1 H), 7.47 (t, J=7.58 Hz, 1 H), 7.18 (brs, 1 H), 6.31 (brs, 1H), 5.16 (brs, 1 H), 4.60 (d, J=8.34 Hz, 2 H), 4.05-3.97 (m, 2 H), 3.82(brs, 2 H), 3.62 (brs, 2 H), 3.17 (m, 2 H), 2.33 (s, 1 H), 1.28-1.13 (m,3 H).

Example 5-11N-(2,2-Difluoroethyl)-N′-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 5-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andN-(2,2-difluoroethyl)ethane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 461,¹H NMR (400 MHz, CD₃OD) δ ppm 7.97 (dd, J=7.83, 1.26 Hz, 1 H), 7.83 (d,J=6.82 Hz, 1 H), 7.60 (td, J=7.45, 1.26 Hz, 2 H), 7.46-7.38 (m, 2 H),7.28 (dd, J=8.59, 1.77 Hz, 1 H), 6.04 (s, 1 H), 5.13 (s, 2 H), 3.58 (t,J=4.80 Hz, 2 H), 3.46 (t, J=6.19 Hz, 2 H), 3.37 (s, 3 H), 3.10-2.97 (m,4 H), 2.41 (s, 3 H).

Example 5-123-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}oxetan-3-ethanol

The title compound was prepared in analogy to Example 5-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and3-aminooxetan-3-ethanol. MS obsd. (ESI⁺) [(M+H)⁺] 454, ¹H NMR (400 MHz,DMSO-d6) δ ppm 7.97 (d, 1 H), 7.89 (d, 1 H), 7.64 (t, 1 H), 7.55 (s, 1H), 7.49-7.42 (m, 2 H), 7.35-7.32 (m, 1 H), 6.63 (s, 1 H), 5.15 (s, 2H), 4.50 (d, 2 H), 4.41 (brs, 2 H), 4.39 (d, 4 H), 3.66 (d, 2 H), 2.33(s, 3 H), 2.27 (t, 2 H).

Example 6-1N-{[3-(Aminomethyl)thietan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A flask containing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (250 mg, 0.67 mmol), thietane-3,3-diyldimethanamine (266 mg,2.01 mmol), tris(dibenzylideneacetone)dipalladium(0) (61.8 mg, 0.067mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (42 mg, 0.067 mmol),sodium tert-butoxide (160 mg, 1.66 mmol) and toluene (15 mL) wasevacuated and then filled with nitrogen (balloon). After being stirredat 110° C. overnight, the resulting mixture was diluted with water (15mL) and extracted with ethyl acetate (15 mL×4). The combined organiclayers were dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by flash column chromatography and preparative HPLCto afford 63 mg of the product as a white solid (yield was 20%). MSobsd. (ESI⁺) [(M+H)⁺] 469, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.96-7.94 (m, 1H), 7.68-7.66 (d, J=7.2 Hz, 1 H), 7.47-7.43 (m, 2 H), 7.31-7.27 (m, 1H), 7.22-7.21 (d, J=1.6 Hz, 1 H), 7.19 (s, 1 H), 5.88 (s, 1 H), 5.07 (s,2 H), 4.50 (s, 2 H), 3.55-3.49 (m, 4 H), 3.11 (s, 2 H), 3.06-3.03 (d,J=9.6 Hz, 2 H), 2.94-2.91 (d, J=9.6 Hz, 2 H), 2.31 (s, 3 H).

Example 6-2N-{[3-(Aminomethyl)-1,1-dioxidothietan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 6-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(1,1-dioxidothietane-3,3-diyl)dimethanamine. MS obsd. (ESI⁺) [(M+H)⁺]501, ¹H NMR (400 MHz, CD₃Cl) δ ppm 7.958-7.939 (d, J=7.6 Hz, 1 H),7.651-7.633 (d, J=7.2 Hz, 1 H), 7.482-7.415 (m, 2 H), 7.308-7.270 (t,J=7.2 Hz, 1 H), 7.235-7.215 (d, J=8.0 Hz, 1 H), 7.134 (s, 1 H), 6.646(s, 1 H), 5.065 (s, 2 H), 4.701-1.250 (brs, 2 H), 3.924-3.890 (m, 4 H),3.659-3.646 (d, J=5.2 Hz, 2 H), 3.491 (s, 2 H), 3.320 (s, 2 H), 2.323(s, 3 H).

Example 7N-(4,5-Dihydro-1H-imidazol-2-yl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (150 mg, 0.40 mmol, prepared in analogy to the one inExample 2-1), hydrogen iodide salt of 4,5-dihydro-1H-imidazol-2-amine(110 mg, 0.515 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(25 mg, 0.043 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg,0.038 mmol), cesium carbonate (525 mg, 1.6 mmol) and 1,4-dioxane (3 mL)was heated with stirring in a 5 mL of microwave process vial for 2 hoursat 120° C. under microwave irradiation. The resulting mixture wasfiltered and washed with ethyl acetate. The filtrate was washed withbrine, dried over sodium sulfate, and concentrated in vacuo. The residuewas purified by preparative HPLC to afford the product as a solid. MSobsd. (ESI⁺) [(M+H)⁺] 422, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.68-7.59 (m, 2H), 7.56 (s, 1 H), 7.50-7.41 (m, 2 H), 7.08 (s, 1 H), 5.23 (brs, 2 H),4.62 (s, 3 H), 3.76 (s, 3 H), 3.61 (t, J=4.93 Hz, 2 H), 2.68 (s, 4 H),2.45 (s, 2 H).

Example 8-1trans-4-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}cyclohexanol

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (140 mg, 0.38 mmol, prepared in analogy to the one inExample 2-1), trans-4-aminocyclohexanol (45 mg, 0.39 mmol),tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (15 mg, 0.038mmol), sodium tert-butoxide (38 mg, 0.39 mmol) and 1,4-dioxane (2 mL)was heated with stirring in a 5 mL of microwave process vial for 2 hoursat 120° C. under microwave irradiation. The mixture was filtered andwashed with ethyl acetate. The filtrate was washed with brine, driedover sodium sulfate, and concentrated in vacuo. The residue was purifiedby preparative HPLC to afford the product as a solid. MS obsd. (ESI⁺)[(M+H)⁺] 452, ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.98-7.83 (m, 2 H), 7.76(s, 1 H), 7.64-7.44 (m, 2 H), 7.29 (d, J=8.34 Hz, 1 H), 7.21 (d, J=8.84Hz, 1 H), 6.22 (d, J=8.34 Hz, 1 H), 6.06 (s, 1 H), 5.09 (brs, 2 H), 4.68(d, J=4.29 Hz, 1 H), 3.62 (brs, 3 H), 3.49 (d, J=4.55 Hz, 1 H), 2.34 (s,3 H), 2.03-1.83 (m, 4 H), 1.63-1.45 (m, 2 H), 1.35 (brs, 2 H), 1.24(brs, 1 H), 1.18 (brs, 1 H).

Example 8-2(2S)-2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol

The title compound was prepared in analogy to Example 8-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(2S)-2-aminopropan-1-ol. MS obsd. (ESI⁺) [(M+H)⁺] 412, ¹H NMR (400 MHz,DMSO-d6) δ ppm 7.89 (t, J=6.32 Hz, 2 H), 7.75 (s, 1 H), 7.64 (t, J=7.20Hz, 1 H), 7.55-7.43 (m, 1 H), 7.38-7.27 (m, 1 H), 7.27-7.14 (m, 1 H),6.16 (d, J=8.08 Hz, 1 H), 6.07 (s, 1 H), 5.07 (brs, 2 H), 4.85 (brs, 1H), 4.42 (brs, 1 H), 3.85 (dt, J=12.82, 6.35 Hz, 1 H), 3.70-3.47 (m, 3H), 2.36 (s, 3 H), 1.23 (d, J=6.32 Hz, 3 H).

Example 8-3trans-1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-methoxypyrrolidin-3-amine

The title compound was prepared in analogy to Example 8-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andtrans-4-methoxy-3-methylpyrrolidin-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]453, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.00 (dd, J=7.83, 1.26 Hz, 1 H),7.89-7.78 (m, 2 H), 7.63 (td, J=7.45, 1.26 Hz, 1 H), 7.53 (d, J=8.59 Hz,1 H), 7.47 (td, J=7.71, 1.01 Hz, 1 H), 7.35 (dd, J=8.59, 1.52 Hz, 1 H),6.19 (s, 1 H), 5.19 (s, 2 H), 4.53 (brs, 2 H), 4.12 (dd, J=11.12, 5.05Hz, 1 H), 3.99-3.81 (m, 2 H), 3.73 (brs, 1 H), 3.67-3.56 (m, 2 H),3.55-3.41 (m, 5 H), 2.43 (s, 3 H).

Example 8-42-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-[trans-4-methoxypyrrolidin-3-yl]-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 8-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andtrans-4-methoxy-3-methylpyrrolidin-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]453, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.14 (d, J=7.83 Hz, 1 H), 8.08 (s, 1H), 7.87 (d, J=7.33 Hz, 1 H), 7.79-7.73 (m, 2 H), 7.69-7.63 (m, 2 H),6.10 (s, 1 H), 5.36 (q, J=16.67 Hz, 2 H), 4.60 (brs, 2 H), 4.28 (brs, 1H), 3.93 (dd, J=12.63, 6.82 Hz, 1 H), 3.82 (t, J=4.80 Hz, 2 H),3.75-3.68 (m, 1 H), 3.68-3.59 (m, 2 H), 3.56 (s, 3 H), 2.51 (s, 3 H).

Example 8-54-{4-[(4aS,7aR)-Hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]-6-methylquinolin-2-yl}-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

The title compound was prepared in analogy to Example 8-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(4aS,7aR)-octahydropyrrolo[3,4-b][1,4]oxazine. MS obsd. (ESI⁺) [(M+H)⁺]465, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.99 (dd, J=7.83, 1.26 Hz, 1 H), 7.85(d, J=7.33 Hz, 1 H), 7.81 (s, 1 H), 7.63 (td, J=7.52, 1.39 Hz, 1 H),7.50-7.41 (m, 2 H), 7.28 (dd, J=8.59, 1.77 Hz, 1 H), 6.09 (s, 1 H), 5.16(s, 2 H), 4.51 (m, 2 H), 4.02-4.15 (m, 3 H), 3.86 (d, J=10.8 Hz, 1 H),3.68-3.47 (m, 6 H), 3.238 (m, 1 H), 2.72 (m, 1 H), 2.41 (s, 3 H).

Example 8-6(3R,4R)-1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-(4-methylpiperazin-1-yl)pyrrolidin-3-ol

The title compound was prepared in analogy to Example 8-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(3R,4R)-4-(4-methylpiperazin-1-yl)pyrrolidin-3-ol. MS obsd. (ESI⁺)[(M+H)⁺] 522, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.99-7.86 (m, 1 H),7.84-7.75 (m, 1 H), 7.73 (s, 1 H), 7.64-7.52 (m, 1 H), 7.47 (d, J=8.59Hz, 1 H), 7.43-7.32 (m, 1 H), 7.27 (d, J=8.59 Hz, 1 H), 6.27-6.09 (m, 1H), 5.10 (brs, 2 H), 4.50 (brs, 1 H), 4.43-4.33 (m, 1 H), 3.81-3.62 (m,2 H), 3.56 (dd, J=9.85, 4.55 Hz, 3 H), 3.45-3.35 (m, 1 H), 3.02-2.92 (m,1 H), 2.84 (brs, 2 H), 2.76-2.62 (m, 3 H), 2.57 (brs, 3 H), 2.39 (s, 3H), 2.32 (s, 3 H).

Example 8-7N-{2-[(2-Aminoethyl)sulfanyl]ethyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 8-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2,2′-sulfanediyldiethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 457, ¹H NMR (400MHz, CD₃OD) δ ppm 8.00 (dd, J=7.83, 1.26 Hz, 1 H), 7.84 (d, J=7.33 Hz, 1H), 7.65 (td, J=7.58, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.51-7.39 (m, 2 H),7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.03 (s, 1 H), 5.14 (s, 2 H), 3.65-3.50(m, 4 H), 2.92-2.79 (m, 4 H), 2.78-2.68 (m, 2 H), 2.42 (s, 3 H).

Example 9-11-{1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidin-4-yl}methanamine

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (75 mg, 0.20 mmol, prepared in analogy to the one in Example2-1), piperidin-4-yl-methylamine (3 mL) in a 2-5 mL of process vial washeated at 160° C. under microwave irradiation for 1 hour. After beingcooled to room temperature, the mixture was concentrated in vacuo toremove the solvent. The residue was purified by preparative HPLC toafford the product as a solid. MS obsd. (ESI⁺) [(M+H)⁺] 451, ¹H NMR (400MHz, DMSO-d6) δ ppm 7.96-7.81 (m, 2 H), 7.66 (td, J=7.58, 1.26 Hz, 1 H),7.53-7.39 (m, 3 H), 7.28 (dd, J=8.72, 1.89 Hz, 1 H), 6.58 (s, 1 H), 5.13(brs, 2 H), 4.42 (brs, 2 H), 3.65 (t, J=4.80 Hz, 2 H), 3.42 (d, J=11.62Hz, 2 H), 2.72 (t, J=10.99 Hz, 2 H), 2.41-2.27 (m, 3 H), 1.95-1.74 (m, 2H), 1.61-1.33 (m, 5 H).

Example 9-2 2-{[2-(8-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}ethanol

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4-dichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and 2-aminoethanol. MS obsd.(ESI⁺) [(M+H)⁺] 414, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.82 (d, J=8.08 Hz, 1H), 7.76 (d, J=8.34 Hz, 1 H), 7.53 (d, J=2.78 Hz, 2 H), 7.51-7.41 (m, 1H), 7.22-7.09 (m, 2 H), 6.10 (s, 1 H), 5.11 (s, 2 H), 4.62 (brs, 2 H),3.83 (s, 3 H), 3.91-3.80 (m, 2 H), 3.61 (brs, 2 H), 3.52 (t, J=5.81 Hz,2 H).

Example 9-3N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andpropane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.96 (dd, J=7.83, 1.01 Hz, 1 H), 7.81 (d, J=7.07 Hz, 1 H),7.64-7.54 (m, 2 H), 7.47-7.35 (m, 2 H), 7.26 (dd, J=8.59, 1.77 Hz, 1 H),5.98 (s, 1 H), 5.12 (s, 2 H), 3.56 (t, J=4.93 Hz, 2 H), 3.39 (t, J=6.82Hz, 2 H), 2.82 (t, J=6.95 Hz, 2 H), 2.39 (s, 3 H), 1.89 (t, J=6.95 Hz, 2H).

Example 9-44-[6-Methyl-4-(morpholin-4-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andmorpholine. MS obsd. (ESI⁺) [(M+H)⁺] 424, ¹H NMR (400 MHz, CDCl₃) δ ppm8.06 (d, J=8.0 Hz, 1 H), 7.62-7.53 (m, 4 H), 7.40 (t, J=7.6 Hz, 1 H),7.32 (d, J=7.6 Hz, 1 H), 6.42 (s, 1 H), 5.51 (s, 2 H), 4.60 (brs, 2 H),4.00 (t, J=4.4 Hz, 4 H), 3.59 (s, 2 H), 3.10 (m, 4 H), 2.44 (s, 3 H).

Example 9-53-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and3-propan-1-ol. MS obsd. (ESI⁺) [(M+H)⁺] 412, ¹H NMR (400 MHz, CDCl₃) δppm 8.02 (d, J=7.2 Hz, 1 H), 7.71 (m, 1 H), 7.53-7.49 (m, 2 H), 7.38 (t,J=7.2 Hz, 1 H), 7.26 (m, 2 H), 5.31 (s, 1 H), 5.13 (s, 2 H), 4.60 (brs,2 H), 3.92 (t, J=4.2 Hz, 2 H), 3.52 (s, 2 H), 3.44 (m, 2 H), 2.40 (s, 3H), 2.00 (m, 2 H).

Example 9-62-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(piperidin-1-yl)ethyl]quinolin-4-amine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2-(piperidin-1-yl)ethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 465, ¹H NMR (400MHz, CDCl₃) δ ppm 8.04 (d, J=7.6 Hz, 1 H), 7.67 (d, J=7.6 Hz, 1 H), 7.51(m, 2 H), 7.38 (t, J=7.6 Hz, 1 H), 7.30 (m, 2 H), 5.74 (m, 1 H), 5.12(s, 2 H), 4.6 (brs, 2 H), 3.58 (s, 2 H), 3.28 (m, 2 H), 2.75 (t, J=8.4Hz, 2 H), 2.46 (m, 7 H), 1.62 (m, 4 H), 1.52 (m, 2 H).

Example 9-71-Amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-2-ol

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and1,3-diaminopropan-2-ol. MS obsd. (ESI⁺) [(M+H)⁺] 427, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.97 (d, J=2.0 Hz, 1 H), 7.86 (d, J=1.8 Hz, 1 H), 7.62 (t,J=3.7 Hz, 1 H), 7.57 (s, 1 H), 7.44 (t, J=3.8 Hz, 2 H), 7.30-7.27 (m,J=2.5 Hz, 1 H), 6.09 (s, 1 H), 5.15 (s, 2 H), 4.53 (brs, 2 H), 3.97-3.91(m, J=5.8 Hz, 2 H), 3.58 (t, J=2.4 Hz, 2 H), 3.66-3.41 (m, J=3.3 Hz, 2H), 2.90 (dd, J=4.2, 0.90 Hz, 1 H), 2.77 (dd, J=5.2, 0.9 Hz, 1 H), 2.42(s, 3 H).

Example 9-8N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and glycine.MS obsd. (ESI⁺) [(M+H)⁺] 412, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.01 (d,J=1.8 Hz, 1 H), 7.89 (d, J=1.9 Hz, 1 H), 7.68 (t, J=2.9 Hz, 2 H), 7.54(d, J=2.1 Hz, 1 H), 7.48 (t, J=2.2 Hz, 1 H), 7.40 (d, J=0.9 Hz, 1 H),5.73 (s, 1 H), 5.09 (s, 2 H), 4.36 (brs, 2 H), 3.3 (s, 2 H), 3.58 (s, 2H), 2.41 (s, 3 H).

Example 9-9N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-fluoroquinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-fluoroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4-dichloro-6-fluoroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd.(ESI⁺) [(M+H)⁺] 401, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (d, J=7.6 Hz, 1H), 7.84 (d, J=7.6 Hz, 1 H), 7.64 (t, J=7.6 Hz, 1 H), 7.58 (dd, J=2.8,10.8 Hz, 1 H), 7.52 (dd, J=6.4, 8.8 Hz, 1 H), 7.45 (t, J=8.0 Hz, 1 H),7.22 (td, J=2.8, 8.8 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 4.55 (brs,2 H), 3.63-3.57 (m, 2 H), 3.43 (t, J=6.4 Hz, 2 H), 2.97 (t, J=6.4 Hz, 2H).

Example 9-10N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-ethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 4-chloro-6-ethylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd.(ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (d, J=7.6 Hz, 1H), 7.84 (d, J=7.6 Hz, 1 H), 7.62 (m, 2 H), 7.44 (t, J=8.4 Hz, 2 H),7.32 (dd, J=1.6, 8.4 Hz, 1 H), 6.03 (s, 1 H), 5.14 (s, 2 H), 4.53 (brs,2 H), 3.58 (s, 2 H), 3.44 (t, J=6.0 Hz, 2 H), 2.97 (t, J=6.4 Hz, 2 H),2.72 (q, J=7.6 Hz, 2 H), 1.27 (t, J=7.6 Hz, 3 H).

Example 9-11N-[7-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4,7-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4,7-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and propane-1,3-diamine. MSobsd. (ESI⁺) [(M+H)⁺] 431, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.10-8.05 (m, 2H), 7.91-7.82 (m, 2 H), 7.80-7.69 (m, 1 H), 7.61-7.50 (m, 1 H),7.43-7.41 (d, J=7.6 Hz, 1 H), 5.95 (s, 1 H), 5.30 (s, 2 H), 4.5 (s, 2H), 3.72 (s, 2 H), 3.59-3.56 (t, J=6.4 Hz, 2 H), 3.10-3.06 (t, J=7.6 Hz,2 H), 2.70-2.10 (t, J=7.2 Hz, 2 H).

Example 9-12N-[8-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4,8-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4,8-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and propane-1,3-diamine. MSobsd. (ESI⁺) [(M+H)⁺] 431, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.08-8.05 (m, 2H), 7.94-7.92 (d, J=7.6 Hz, 1 H), 7.85-7.83 (d, J=7.6 Hz, 1 H),7.71-7.70 (m, 1 H), 7.57-7.56 (m, 1 H), 7.41-7.38 (m, 1 H), 6.00 (s, 1H), 5.39 (s, 2 H), 4.55 (s, 2 H), 3.74 (s, 2 H), 3.60-3.56 (t, J=6.8 Hz,2 H), 3.09-3.05 (t, J=7.6 Hz, 2 H), 2.11-2.07 (m, 2 H).

Example 9-13N-[5-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4,5-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4,5-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and propane-1,3-diamine. MSobsd. (ESI⁺) [(M+H)⁺] 431, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.08-8.06 (d,J=7.6 Hz, 1 H), 7.94-7.92 (m, 2 H), 7.41-7.26 (m, 5 H), 5.99 (s, 1 H),5.35 (s, 2 H), 4.55 (s, 2 H), 3.74 (s, 2 H), 3.63-3.61 (m, 2 H),3.15-3.11 (t, J=7.6 Hz, 2 H), 2.16-2.13 (m, 2 H).

Example 9-14N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2-dimethylpropane-1,3-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2,2-dimethylpropane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 439, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.07 (d, J=1.2 Hz, 1 H), 7.99 (s, 1 H), 7.88 (d,J=7.2 Hz, 1 H), 7.73-7.70 (m, 2 H), 7.61-7.57 (m, 2 H), 6.07 (s, 1 H),5.31 (s, 2 H), 4.50 (s, 2 H), 3.73 (s, 2 H), 3.49 (s, 2 H), 2.99 (s, 2H), 2.47 (s, 3 H), 1.10 (s, 6 H).

Example 9-15N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4-dichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd.(ESI⁺) [(M+H)⁺] 383, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.87 (m, 1 H), 7.81(d, J=7.83 Hz, 2 H), 7.55 (m, 1 H), 7.47 (m, 1 H), 7.33 (m, 2 H), 7.04(m, 1 H), 5.94 (m, 1 H), 5.12 (s, 2 H), 3.57 (t, J=4.55 Hz, 2 H), 3.43(t, J=6.32 Hz, 2 H), 3.33 (m, 2 H), 2.97 (t, J=6.44 Hz, 2 H).

Example 9-16N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andethane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 397, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.86 (m, 2 H), 7.65-7.50 (m, 2 H), 7.42-7.30 (m, 2 H),7.28-7.16 (m, 1 H), 6.10-5.95 (m, 1 H), 5.09 (brs, 2 H), 3.64-3.42 (m, 2H), 3.15-2.98 (m, 2 H), 2.84 (s, 2 H), 2.35 (s, 3 H), 1.20 (s, 2 H).

Example 9-17N^(˜)2^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2-methylpropane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 425, ¹H NMR (400MHz, CD₃OD) δ ppm 7.98 (dd, J=7.83, 1.26 Hz, 1 H), 7.86 (d, J=6.82 Hz, 1H), 7.70 (s, 1 H), 7.61 (td, J=7.45, 1.26 Hz, 1 H), 7.47-7.42 (m, 2 H),7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 3.58 (t,J=4.80 Hz, 2 H), 3.33 (m, 2 H), 3.27 (s, 2 H), 2.43 (s, 3 H), 1.27 (s, 6H).

Example 9-18N^(˜)2^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andpropane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.97 (dd, J=7.83, 1.01 Hz, 1 H), 7.82 (d, J=7.33 Hz, 1 H),7.69-7.56 (m, 2 H), 7.46-7.38 (m, 2 H), 7.28 (dd, J=8.46, 1.64 Hz, 1 H),6.11-5.96 (m, 1 H), 5.13 (s, 2 H), 3.66-3.49 (m, 2 H), 3.30-3.20 (m, 3H), 2.47-2.39 (m, 3 H), 2.24-2.19 (m, 2 H), 1.32-1.22 (m, 3 H).

Example 9-19 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]butane-1,4-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andbutane-1,4-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 425, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.01-7.95 (m, 1 H), 7.92-7.86 (m, 1 H), 7.83-7.76 (m, 1 H),7.69-7.61 (m, 1 H), 7.61-7.54 (m, 1 H), 7.50-7.42 (m, 1 H), 7.39-7.31(m, 1 H), 5.96 (s, 1 H), 5.20 (brs, 2 H), 3.63 (brs, 2 H), 3.47 (brs, 2H), 3.37 (s, 2 H), 2.42 (s, 3 H), 2.27-2.24 (m, 4 H), 1.86 (d, J=3.28Hz, 2 H).

Example 9-20N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-nitroquinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-nitroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4-dichloro-6-nitroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd.(ESI⁺) [(M+H)⁺] 428, ¹H NMR (400 MHz, CD₃OD) δ ppm 9.07 (d, J=2.53 Hz, 1H), 8.13 (dd, J=9.35, 2.53 Hz, 1 H), 7.96 (d, J=7.58 Hz, 1 H), 7.91 (dd,J=7.71, 1.14 Hz, 1 H), 7.69 (t, J=7.20 Hz, 1H), 7.56-7.41 (m, 2 H), 6.09(s, 1 H), 5.15 (brs, 2 H), 3.64 (brs, 2 H), 3.34 (brs, 4 H), 2.79 (t,J=6.44 Hz, 2 H).

Example 9-21N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-5-fluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,4-dichloro-5-fluoro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd.(ESI⁺) [(M+H)⁺] 415, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98-7.83 (m, 2 H),7.71-7.60 (m, 1 H), 7.53-7.43 (m, 1 H), 7.32-7.22 (m, 1 H), 7.21-7.11(m, 1 H), 6.80-6.66 (m, 1 H), 6.01 (s, 1 H), 5.08 (brs, 2 H), 3.61 (t,J=4.67 Hz, 2 H), 3.31-3.26 (m, 3 H), 2.87 (t, J=6.19 Hz, 2 H), 2.22 (d,J=2.53 Hz, 3 H).

Example 9-222-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-yl]amino}ethanol

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-5-fluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 9-21) andaminoethanol. MS obsd. (ESI⁺) [(M+H)⁺] 416, ¹H NMR (400 MHz, DMSO-d6) δppm 7.94-7.84 (m, 2 H), 7.66 (td, J=7.45, 1.26 Hz, 1 H), 7.49 (td,J=7.71, 1.26 Hz, 1 H), 7.32-7.21 (m, 1 H), 7.21-7.11 (m, 1 H), 6.48 (dt,J=16.93, 4.67 Hz, 1 H), 6.04 (s, 1 H), 5.08 (brs, 2 H), 4.98 (t, J=5.18Hz, 1 H), 3.67 (q, J=5.31 Hz, 2 H), 3.61 (t, J=4.80 Hz, 2 H), 3.43 (m, 2H), 2.22 (d, J=2.53 Hz, 3 H).

Example 9-232-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-fluoro-6-methylquinolin-4-yl]amino}ethanol

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-7-fluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,4-dichloro-7-fluoro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and aminoethanol. MS obsd.(ESI⁺) [(M+H)⁺] 416, ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.93-7.87 (m, 2 H),7.84 (d, J=8.84 Hz, 1 H), 7.65 (td, J=7.52, 1.14 Hz, 1 H), 7.53-7.43 (m,1 H), 7.05 (d, J=11.87 Hz, 1 H), 6.71 (t, J=5.56 Hz, 1 H), 6.00 (s, 1H), 5.07 (brs, 2 H), 4.83 (t, J=5.56 Hz, 1 H), 3.67-3.55 (m, 4 H),3.42-3.36 (m, 2 H), 2.27 (s, 3 H).

Example 9-24N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-fluoro-6-methylquinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-7-fluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,4-dichloro-7-fluoro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd.(ESI⁺) [(M+H)⁺] 415, ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.93 (d, J=6.82 Hz,1 H), 7.91-7.87 (m, 1 H), 7.82 (d, J=8.84 Hz, 1 H), 7.66 (td, J=7.52,1.39 Hz, 1 H), 7.48 (td, J=7.71, 1.01 Hz, 1 H), 7.09-7.03 (m, 1 H), 5.99(s, 1 H), 5.09 (brs, 2 H), 3.61 (m, 2 H), 3.45-3.31 (m, 4 H), 2.90 (t,J=6.32 Hz, 2 H), 2.27 (s, 3 H).

Example 9-25N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7,8-difluoro-6-methylquinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-7,8-difluoro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,4-dichloro-7,8-difluoro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd.(ESI⁺) [(M+H)⁺] 433, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (m, 1 H), 8.08(m, 1 H), 7.84 (m, 1 H), 7.76 (m, 1 H), 7.53 (m, 1 H), 5.99 (s, 1 H),5.06 (brs, 2 H), 3.70 (m, 2 H), 3.49-3.30 (m, 4 H), 3.01 (m, 2 H), 2.92(s, 3 H).

Example 9-262-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-(2-methoxyethyl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2-methoxyethaneamine. MS obsd. (ESI⁺) [(M+H)⁺] 412, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.12-8.08 (d, J=7.6 Hz, 1 H), 7.90 (s, 1 H), 7.35-7.30 (d,J=7.6 Hz, 1 H), 7.26-7.13 (m, 2 H), 7.11-7.05 (m, 2 H), 6.06 (s, 1 H),5.27 (s, 2 H), 4.50 (s, 2 H), 4.78-4.62 (m, 6 H), 3.35 (s, 3 H), 2.45(s, 3 H).

Example 9-271-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidin-4-amine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andpiperidin-4-amine. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR (400 MHz, CD₃OD)δ ppm 8.10-8.08 (m, 1 H), 7.84-7.71 (m, 3 H), 7.62-7.59 (m, 3 H), 6.50(s, 1 H), 5.34 (s, 2 H), 4.57-4.55 (m, 2 H), 3.96-3.86 (m, 2 H),3.78-3.76 (m, 2 H), 3.48-3.45 (m, 1 H), 3.13-3.08 (m, 2 H), 2.48 (s, 3H), 2.27-2.23 (m, 2 H), 2.02-1.92 (m, 2 H).

Example 9-281-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]pyrrolidin-3-amine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-1,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloro-1,6-naphthyridine) and pyrrolidin-3-amine. MS obsd. (ESI⁺)[(M+H)⁺] 410, ¹H NMR (400 MHz, CD₃OD) δ ppm 9.26 (s, 1 H), 8.28-8.20 (d,J=6.4 Hz, 1 H), 8.05-7.98 (d, J=8 Hz, 1 H), 7.90-7.82 (d, J=7.2 Hz, 1H), 7.70-7.60 (m, 2 H), 7.50-7.42 (t, J=7.2 Hz, 1 H), 6.14 (s, 1 H),5.26 (s, 2 H), 4.70-4.50 (m, 2 H), 4.20-4.10 (m, 2 H), 4.10-4.00 (m, 1H), 3.90-3.78 (m, 2 H), 3.60-3.52 (t, J=2.8 Hz, 2 H), 2.60-2.48 (m, 1H), 2.35-2.25 (m, 1 H).

Example 9-29N-[6-(Difluoromethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-difluoromethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

(prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,4-dichloro-6-difluoromethylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and propane-1,3-diamine. MSobsd. (ESI⁺) [(M+H)⁺] 447, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.39 (s, 1 H),8.12-8.08 (d, J=7.6 Hz, 1 H), 7.95-7.85 (m, 3 H), 7.78-7.70 (t, J=1.2Hz, 1 H), 7.65-7.58 (t, J=6.8 Hz, 1 H), 7.03-6.72 (t, J=54.4 Hz, 1 H),6.03 (s, 1 H), 5.35 (s, 2 H), 4.60-4.49 (m, 2 H), 3.80-3.72 (t, J=2.8Hz, 2 H), 3.68-3.60 (t, J=6.8 Hz, 2 H), 3.15-3.09 (t, J=7.6 Hz, 2 H),2.16-2.05 (m, 2 H).

Example 9-306-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-ethylquinolin-4-amine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4,6-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethaneamine. MS obsd. (ESI⁺)[(M+H)⁺] 402, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (s, 1 H), 7.90 (t,J=4.2 Hz, 2 H), 7.65 (t, J=3.5 Hz, 1 H), 7.48 (t, J=3.7 Hz, 1 H), 7.38(t, J=3.8 Hz, 2 H), 6.03 (s, 1 H), 5.09 (s, 2 H), 4.42 (brs, 2 H), 3.62(t, J=2.4 Hz, 2 H), 3.3 (m, 2 H), 1.24 (t, 3 H).

Example 9-312-{[6-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}ethanol

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4,6-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and aminoethanol. MS obsd.(ESI⁺) [(M+H)⁺] 418, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (s, 1 H), 7.90(t, J=3.9 Hz, 2 H), 7.65 (t, J=3.7 Hz, 1 H), 7.49 (t, J=3.8 Hz, 1 H),7.39 (t, J=3.6 Hz, 2 H), 6.83 (t, J=4.6 Hz, 1 H), 6.08 (s, 1 H), 5.08(s, 2 H), 4.81 (t, J=2.8 Hz, 1 H), 4.43 (brs, 2 H), 3.63 (m, 4 H), 3.85(m, 2 H).

Example 9-32N-[6-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-N′-methylethane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4,6-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and N-methylethane-1,2-diamine.MS obsd. (ESI⁺) [(M+H)⁺] 431, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (d,J=2.0 Hz, 1 H), 7.90 (s, 1 H), 7.84 (d, J=1.8 Hz, 1 H), 7.63 (t, J=3.7Hz, 1 H), 7.46 (t, J=4.1 Hz, 2 H), 7.36 (m, J=2.8 Hz, 1 H), 6.08 (s, 1H), 5.17 (s, 2 H), 4.55 (brs, 2 H), 3.58 (t, J=2.3 Hz, 2 H), 3.50 (t,J=3.1 Hz, 2 H), 2.96 (t, J=3.1 Hz, 2 H), 2.51 (s, 3 H).

Example 9-33N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(methylsulfanyl)quinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(4-chloro-6-(methylsulfanyl)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,4-dichloro-6-(methylsulfanyl)quinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and propane-1,3-diamine. MSobsd. (ESI⁺) [(M+H)⁺] 442, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.07 (dd,J=1.2, 8.0 Hz, 1 H), 7.92 (d, J=2.0 Hz, 1 H), 7.84 (d, J=7.6 Hz, 1 H),7.74-7.69 (m, 2 H), 7.64 (dd, J=2.0, 8.8 Hz, 1 H), 7.57 (t, J=8.0 Hz, 1H), 5.95 (s, 1 H), 5.30 (s, 2 H), 4.50 (brs, 2 H), 3.72 (t, J=4.8 Hz, 2H), 3.59 (t, J=6.8 Hz, 2 H), 3.08 (t, J=7.6 Hz, 2 H), 2.55 (s, 3 H),2.14-2.05 (m, 2 H).

Example 9-34N-[6-Bromo-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 6-bromo-2,4-dichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and propane-1,3-diamine. MSobsd. (ESI⁺) [(M+H)⁺] 475, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.34 (s, 1 H),8.05-8.04 (d, J=7.6 Hz, 1 H), 7.88-7.86 (d, J=7.6 Hz, 1 H), 7.81-7.79(d, J=9.2 Hz, 1 H), 7.75-7.69 (m, 2 H), 7.58-7.55 (t, J=7.6 Hz, 1 H),5.98 (s, 2 H), 5.34 (s, 2 H), 4.52 (s, 2 H), 3.72 (s, 2 H), 3.60-3.57(t, J=7.2 Hz, 2 H), 3.12-3.08 (t, J=7.6 Hz, 2 H), 2.15-2.08 (m, 2 H).

Example 10{4-[(2-Aminoethyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}methanol

4-Chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanol

The title compound was prepared in analogy to4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanolin Example 3-23 in Scheme 5 by using methyl4-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate(prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepinein Example 1-1 in Scheme 4 by using methyl 2,4-dichloroquinoline-6-carboxylate and 2,3,4,5-tetrahydro-1,4-benzothiazepine) andsodium borohydride.

{4-[(2-Aminoethyl)amino]-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}methanol

The title compound was prepared in analogy to Example 9-1 in Scheme 5 byusing[4-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanoland propane-1,3-diamine.

{4-[(2-Aminoethyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}methanol

To a suspension of{4-[(2-aminoethyl)amino]-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}methanol(370 mg, 1.04 mmol) in dichloromethane (10 mL) was added3-chloroperoxybenzoic acid (384 mg, 2.18 mmol). The resulting mixturewas stirred at room temperature for 2 hours. To the mixture was added anaqueous solution of saturated sodium bicarbonate (1 mL) to quench thereaction, and resulting mixture was diluted with dichloromethane (15mL). The organic phase was separated, washed with saturated sodiumbicarbonate and brine, dried over sodium sulfate, and concentrated invacuo. The residue was purified by flash chromatography to afford 400 mgof the title compound as a yellow solid (yield was 98%). MS obsd. (ESI⁺)[(M+H)⁺] 413, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.18 (s, 1 H), 7.93 (d,J=7.6 Hz, 1 H), 7.87-7.84 (m, 2 H), 7.64 (m, 1 H), 7.45 (m, 1 H), 7.37(s, 1 H), 7.33 (s, 1 H), 6.10 (s, 1 H), 5.09 (s, 2 H), 4.52 (brs, 2 H),3.62 (s, 2 H), 3.37-3.28 (m, 4 H), 3.18 (m, 2 H).

Example 11-12-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,3-diol

A solution of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (200.0 mg, 0.54 mmol, prepared in analogy to the one inExample 2-1) and 2-aminopropane-1,3-diol (420.0 mg, 4.6 mmol) in1-methyl-2-pyrrolidinone (1.0 mL) was stirred at 160° C. for 16 hours.After being cooled to room temperature and diluted with water (50 mL),the resulting mixture was extracted with ethyl acetate (100 mL), washedwith brine (50 mL×2), dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by preparative HPLC toafford 34.6 mg of the product as a white solid (yield was 15%). MS obsd.(ESI⁺) [(M+H)⁺] 428, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.99 (dd, J=7.83,1.01 Hz, 1 H), 7.86 (d, J=7.07 Hz, 1 H), 7.71-7.58 (m, 2 H), 7.51-7.40(m, 2 H), 7.36-7.24 (m, 1 H), 6.16 (s, 1 H), 5.16 (s, 2 H), 4.79-4.59(m, 1 H), 4.54 (brs, 1 H), 3.81 (s, 5 H), 3.69-3.50 (m, 2 H), 2.42 (s, 3H).

Example 11-22,2′-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]imino}diethanol

The title compound was prepared in analogy to Example 11-1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and2,2′-iminodiethanol. MS obsd. (ESI⁺) [(M+H)⁺] 442, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.99 (dd, J=7.83, 1.26 Hz, 1 H), 7.81 (s, 1 H), 7.83 (s, 1H), 7.63 (td, J=7.58, 1.26 Hz, 1 H), 7.56-7.39 (m, 2 H), 7.30 (dd,J=8.46, 1.89 Hz, 1 H), 6.78 (s, 1 H), 5.18 (s, 2 H), 4.57 (brs, 2 H),3.73-3.56 (m, 6 H), 3.56-3.43 (m, 4 H), 2.42 (s, 3 H).

Example 11-34-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-3-hydroxybutanoicacid

The title compound was prepared in analogy to Example 11-1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and4-amino-3-hydroxybutanoic acid. MS obsd. (ESI⁺) [(M+H)⁺] 456. ¹H NMR(400 MHz, CD₃OD) δ ppm 8.10 (dd, J=7.83, 1.26 Hz, 1 H), 7.83-8.00 (m, 2H), 7.80-7.67 (m, 2 H), 7.67-7.52 (m, 2 H), 6.32 (s, 1 H), 5.43-5.27 (m,2 H), 4.55 (brs, 2 H), 4.39-4.23 (m, 1 H), 3.86-3.66 (m, 3 H), 3.57-3.40(m, 1 H), 2.78-2.63 (m, 2 H), 2.50 (s, 3 H).

Example 11-41-Amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropan-2-ol

The title compound was prepared in analogy to Example 11-1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and1,3-diamino-2-methylpropan-2-ol. MS obsd. (ESI⁺) [(M+H)⁺] 441, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.97 (d, J=7.6 Hz, 1 H), 7.88 (d, J=7.6 Hz, 1 H),7.60 (t, J=7.6 Hz, 1 H), 7.57 (s, 1 H), 7.43 (m, 2 H), 7.29 (dd, J=1.2,8.4 Hz, 1 H), 6.18 (s, 1 H), 5.15 (s, 2 H), 4.53 (brs, 2 H), 3.58 (t,J=4.4 Hz, 2 H), 3.34 (m, 2 H), 2.85-2.76 (m, 2 H), 2.42 (s, 3 H), 1.32(s, 3 H).

Example 12-12-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(morpholin-4-yl)ethyl]quinolin-4-amine

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (50 mg, 0.134 mmol, prepared in analogy to the one inExample 2-1), 2-(morpholin-4-yl)ethanamine (78 mg, 0.67 mmol) andn-butanol (5 mL) was heated with stirring in a 10 mL of microwaveprocess vial for 2 hours at 160° C. under microwave irradiation. Afterbeing cooled to room temperature, the mixture was diluted withdichloromethane and washed with brine. The organic layer was dried oversodium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (eluting with 3% methanol indichloromethane) to afford 35 mg of the product as a light oil (yieldwas 56%). MS obsd. (ESI⁺) [(M+H)⁺] 467, ¹H NMR (400 MHz, CDCl₃) δ ppm8.05 (d, J=7.6 Hz, 1 H), 7.66 (d, J=7.2 Hz, 1 H), 7.53-7.51 (m, 2 H),7.38 (m, 1 H), 7.32 (m, 1 H), 5.88 (s, 1 H), 5.56 (s, 2 H), 5.09 (s, 2H), 4.6 (brs, 2 H) 3.76 (t, J=4.8 Hz, 4 H), 3.50 (brs, 2 H), 3.33 (m, 2H), 2.82 (m, 2 H), 2.56 (m, 4 H), 2.29 (s, 3 H).

Example 12-22-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]amino}ethanol

The title compound was prepared in analogy to Example 12-1 in Scheme 5by using4-(4-chloro-1,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloro-1,6-naphthyridine) and 2-aminoethanol. MS obsd. (ESI⁺)[(M+H)⁺] 385, ¹H NMR (400 MHz, CD₃OD) δ ppm 9.66 (s, 1 H), 8.66-8.64 (d,J=6.8 Hz, 1 H), 8.26-8.24 (d, J=6.8 Hz, 1 H), 8.05-8.03 (d, J=7.6 Hz, 1H), 7.97-7.95 (d, J=7.2 Hz, 1 H), 7.71-7.69 (d, J=7.2 Hz, 1 H),7.56-7.54 (d, J=7.6 Hz, 1 H), 6.30 (s, 1 H), 5.38 (s, 1 H), 4.72-4.60(m, 2 H), 3.87-3.86 (m, 2 H), 3.71-3.67 (m, 4 H).

Example 12-3N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]nonane-1,9-diamine

The title compound was prepared in analogy to Example 12-1 in Scheme 5by using4-(4-chloro-8-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4-dichloro-8-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and nonane-1,9-diamine. MS obsd.(ESI⁺) [(M+H)⁺] 495, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.04-8.03 (m, 1 H),7.93-7.91 (m, 1 H), 7.82-7.80 (m, 1 H), 7.68-7.70 (m, 1 H), 7.58-7.56(m, 2 H), 7.40-7.30 (m, 1 H), 5.87 (s, 1 H), 5.30 (s, 2 H), 4.49 (s, 2H), 3.76-3.75 (m, 2 H), 3.42-3.40 (m, 2 H), 2.90-2.85 (m, 2 H), 2.61 (s,3 H), 1.70-1.58 (m, 4 H), 1.48-1.31 (m, 10 H).

Example 12-4N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]decane-1,10-diamine

The title compound was prepared in analogy to Example 12-1 in Scheme 5by using4-(4-chloro-8-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4-dichloro-8-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and decane-1,10-diamine. MSobsd. (ESI⁺) [(M+H)⁺] 509, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.08-8.06 (m, 1H), 7.94-7.93 (m, 1 H), 7.82-7.81 (m, 1 H), 7.72-7.70 (m, 1 H),7.59-7.57 (m, 2 H), 7.42-7.32 (m, 1 H), 5.89 (s, 1 H), 5.31 (s, 2 H),4.50 (s, 2 H), 3.78-3.77 (m, 2 H), 3.44-3.42 (m, 2 H), 2.91-2.87 (m, 2H), 2.63 (s, 3 H), 1.70-1.58 (m, 4 H), 1.48-1.31 (m, 12 H).

Example 12-5N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]octane-1,8-diamine

The title compound was prepared in analogy to Example 12-1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andoctane-1,8-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 481, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.10-8.08 (dd, J=1.2 Hz, 1 H), 7.92 (s, 1 H), 7.86-7.84 (d,J=7.6 Hz, 1 H), 7.71-7.67 (m, 2 H), 7.61-7.55 (m, 2 H), 5.92 (s, 1 H),5.28 (s, 2 H), 4.52 (s, 2 H), 3.75-3.73 (m, 2 H), 3.50-3.46 (t, 2 H),2.93-2.83 (t, 2 H), 2.46 (s, 3 H), 1.74-1.64 (m, 4 H), 1.51-1.40 (m, 8H).

Example 12-69-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}nonan-1-ol

The title compound was prepared in analogy to Example 12-1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and9-aminononanol. MS obsd. (ESI⁺) [(M+H)⁺] 495, ¹H NMR (400 MHz, CD₃OD) δppm 8.11-8.09 (dd, J=1.2 Hz, 1 H), 7.92 (s, 1 H), 7.85-7.83 (d, J=7.6Hz, 1 H), 7.71-7.67 (m, 2 H), 7.61-7.57 (m, 2 H), 5.92 (s, 1 H), 5.28(s, 2 H), 4.52 (s, 2 H), 3.74 (s, 2 H), 3.50-3.46 (t, 2 H), 2.92-2.89(t, 2 H), 2.46 (s, 3 H), 1.73-1.63 (m, 4 H), 1.50-1.38 (m, 10 H).

Example 12-7N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]octane-1,8-diamine

The title compound was prepared in analogy to Example 12-1 in Scheme 5by using4-(4-chloro-8-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4-dichloro-8-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and octane-1,8-diamine. MS obsd.(ESI⁺) [(M+H)⁺] 481, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.09-8.07 (d, J=7.6Hz, 1 H), 7.96-7.94 (d, J=8.4 Hz, 1 H), 7.85-7.83 (d, J=7.6 Hz, 1 H),7.73-7.70 (m, 2 H), 7.36-7.32 (m, 2 H), 5.90 (s, 1 H), 5.33 (s, 2 H),4.52-4.51 (m, 2 H), 3.81-3.78 (t, 2 H), 3.47-3.42 (t, 2 H), 2.91-2.89(t, 2 H), 2.64 (s, 3 H), 1.67-1.63 (m, 4 H), 1.50-1.37 (m, 8 H).

Example 13cis-4-amino-1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (740 mg, 2.0 mmol, prepared in analogy to the one in Example2-1) and cis-4-aminopyrrolidin-3-ol (600 mg, 6.0 mmol) in n-butanol (0.2mL) was heated at 180° C. for 3 days. After being cooled to roomtemperature, the mixture was purified by preparative HPLC to afford theproduct as a solid. MS obsd. (ESI⁺) [(M+H)⁺] 439, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.12 (dd, J=7.83, 1.26 Hz, 1 H), 8.02 (s, 1 H), 7.87 (d,J=7.07 Hz, 1 H), 7.82-7.71 (m, 2 H), 7.67-7.57 (m, 2 H), 5.93 (s, 1 H),5.33 (s, 2 H), 4.66 (d, J=2.02 Hz, 1 H), 4.56 (brs, 2 H), 4.28-4.17 (m,2 H), 4.13-3.99 (m, 2 H), 3.91 (s, 1 H), 3.76 (brs, 2 H), 3.37 (s, 3 H),2.50 (s, 3 H).

Example 14-1N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-L-alanine

The mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (150 mg, 0.40 mmol, prepared in analogy to the one inExample 2-1) and L-alanine (360 mg, 4.0 mmol) in phenol (360 mg) washeated at 150° C. overnight. After being cooled to room temperature, themixture was purified by preparative HPLC to afford the pure product as asolid. MS obsd. (ESI⁺) [(M+H)⁺] 426, ¹H NMR (400 MHz, CD₃OD) δ ppm8.16-7.92 (m, 3 H), 7.84 (d, J=8.34 Hz, 1 H), 7.78-7.62 (m, 1 H),7.61-7.42 (m, 2 H), 5.86 (s, 1 H), 5.24 (brs, 2 H), 4.65-4.35 (m, 3 H),3.69 (brs, 2 H), 3.37 (s, 3 H), 2.53-2.39 (m, 3 H), 1.76-1.57 (m, 3 H).

Example 14-2N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-1]-beta-alanine

The title compound was prepared in analogy to Example 14-1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andbeta-alanine. MS obsd. (ESI⁺) [(M+H)⁺] 426, ¹H NMR (400 MHz, CD₃OD) δppm 8.14-8.08 (m, 1 H), 7.96-7.88 (m, 2 H), 7.77-7.68 (m, 2 H),7.65-7.57 (m, 2 H), 6.09 (s, 1 H), 5.32 (s, 2 H), 4.56 (brs, 1 H),3.84-3.71 (m, 4 H), 3.37 (s, 2 H), 2.76 (t, J=6.95 Hz, 2 H), 2.48 (s, 3H).

Example 15-1N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]benzene-1,3-diamine

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (150 mg, 0.40 mmol, prepared in analogy to the one inExample 2-1), benzene-1,3-diamine (86 mg, 0.80 mmol), palladium acetate(18 mg, 0.04 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (50mg, 0.04 mmol), potassium phosphate (169.6 mg, 0.8 mmol) and 1,4-dioxane(3 mL) in a 2-5 mL of process vial was heated at 140° C. under microwaveirradiation for 1.5 hours. After being cooled to room temperature, themixture was filtered and washed with ethyl acetate. The filtrate waswashed with brine, dried over sodium sulfate, and concentrated in vacuo.The residue was purified by preparative HPLC to afford the pure productas a solid. MS obsd. (ESI⁺) [(M+H)⁺] 445, ¹H NMR (400 MHz, DMSO-d6) δppm 8.31 (s, 1 H), 7.88 (dd, J=6.06, 1.52 Hz, 2 H), 7.63 (td, J=7.52,1.14 Hz, 1 H), 7.54-7.46 (m, 1 H), 7.42-7.33 (m, 2 H), 7.33-7.27 (m, 1H), 7.16 (t, J=7.83 Hz, 1 H), 6.52 (t, J=1.89 Hz, 1 H), 6.49-6.34 (m, 3H), 5.23 (s, 2 H), 4.86 (s, 2 H), 3.60 (brs, 2 H), 2.38 (s, 3 H).

Example 15-2N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]benzene-1,4-diamine

The title compound was prepared in analogy to Example 15-1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1 1) andbenzene-1,4-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 445, ¹H NMR (400 MHz,DMSO-d6) δ ppm 8.21 (s, 1 H), 7.92-7.83 (m, 2 H), 7.63-7.55 (m, 1 H),7.53-7.46 (m, 1 H), 7.34 (d, J=8.34 Hz, 1 H), 7.27 (dd, J=8.59, 1.52 Hz,1 H), 7.15 (d, J=7.58 Hz, 1 H), 6.91 (m, J=8.34 Hz, 2 H), 6.77 (m,J=8.59 Hz, 2 H), 5.97 (s, 1 H), 5.20-5.12 (m, 2 H), 4.76 (brs, 2 H),3.57 (brs, 2 H), 2.37 (s, 3 H).

Example 15-3(3S)-1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol

The title compound was prepared in analogy to Example 15-1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(3S)-pyrrolidin-3-ol. MS obsd. (ESI⁺) [(M+H)⁺] 424, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.90 (dd, J=7.83, 1.26 Hz, 1 H), 7.80-7.72 (m, 2 H), 7.54(td, J=7.52, 1.39 Hz, 1 H), 7.43 (d, J=8.59 Hz, 1 H), 7.34 (td, J=7.71,1.01 Hz, 1 H), 7.23 (dd, J=8.59, 1.77 Hz, 1 H), 6.05 (s, 1 H), 5.06 (s,2 H), 4.55-4.43 (m, 1 H), 3.84 (dd, J=10.48, 4.42 Hz, 2 H), 3.58-3.43(m, 4 H), 3.35 (s, 2 H), 2.35 (s, 3 H), 2.11 (dd, J=8.84, 4.55 Hz, 1 H),2.06-1.97 (m, 1 H).

Example 15-4(3R)-1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol

The title compound was prepared in analogy to Example 15-1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and(3R)-pyrrolidin-3-ol. MS obsd. (ESI⁺) [(M+H)⁺] 424, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.88 (dd, J=7.83, 1.01 Hz, 1 H), 7.79-7.69 (m, 2 H), 7.52(td, J=7.52, 1.14 Hz, 1 H), 7.44 (d, J=8.59 Hz, 1 H), 7.33-7.27 (m, 1H), 7.23 (dd, J=8.59, 1.77 Hz, 1 H), 6.02 (s, 1 H), 5.04 (s, 2 H),4.55-4.42 (m, 2 H), 3.89-3.76 (m, 2 H), 3.59-3.42 (m, 4 H), 3.37 (s, 2H), 2.35 (s, 3 H), 2.16-1.97 (m, 2 H).

Example 15-5trans-N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclopentane-1,2-diamine

The title compound was prepared in analogy to Example 15-1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andtrans-cyclopentane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.03 (d, J=7.83 Hz, 1 H), 7.93-7.81 (m, 2 H),7.67 (t, J=7.45 Hz, 1 H), 7.61 (d, J=8.59 Hz, 1 H), 7.51 (t, J=7.71 Hz,1 H), 7.47 (d, J=7.58 Hz, 1 H), 6.04 (s, 1 H), 5.25 (s, 2 H), 4.66 (brs,1 H), 4.40 (brs, 1 H), 4.27 (d, J=7.07 Hz, 1 H), 3.84 (q, J=7.66 Hz, 1H), 3.75-3.65 (m, 2 H), 2.45 (s, 3 H), 2.40-2.24 (m, 2 H), 2.08-1.79 (m,3 H), 1.58 (dd, J=13.01, 7.71 Hz, 1 H).

Example 16-11-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidin-3-amine

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (0.2 g, 0.54 mmol, prepared in analogy to the one in Example2-1), piperidin-3-ylamine hydrochloric acid salt (0.275 g, 1.6 mmol) andN,N-diisopropylethylamine (1 mL) was heated at 160° C. under microwaveirradiation for 1 hour. After being cooled to room temperature, themixture was purified by preparative HPLC and SPE. After SPE separation,the eluent was concentrated in vacuo to remove the organic solution. Theresidue was dried by lyophylization to give 52.3 mg of the desiredproduct (yield was 22.3%). MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR (400MHz, CD₃OD) δ ppm 8.09-8.07 (d, J=8 Hz, 1 H), 7.87-7.85 (q, J=7.2 Hz, 1H), 7.85-7.82 (m, 1 H), 7.73-7.68 (q, J=14 Hz, 2 H), 7.62-7.55 (m, 2 H),6.56 (s, 1 H), 5.37 (s, 2 H), 4.57 (s, 2 H), 3.90-3.88 (d, J=9.6 Hz, 1H), 3.75 (s, 2 H), 3.67-3.66 (m, 1 H), 3.51-3.48 (d, J=11.6 Hz, 1 H),3.26-3.24 (d, J=9.6 Hz, 1 H), 3.24-3.14 (m, 1 H), 2.49 (s, 3 H),2.26-2.22 (m, 1 H), 2.14-2.10 (m, 1 H), 1.99-1.92 (m, 1 H), 1.91-1.78(m, 1 H).

Example 16-22-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N,N,6-trimethylquinolin-4-amine

The title compound was prepared in analogy to Example 16-1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) anddimethylamine. MS obsd. (ESI⁺) [(M+H)⁺] 382, ¹H NMR (400 MHz, CD₃OD) δppm 8.07 (d, J=7.6 Hz, 1 H), 7.85-7.83 (m, 2 H), 7.73-7.70 (m, 2 H),7.58-7.55 (m, 2 H), 6.14 (s, 1 H), 5.30 (s, 2 H), 4.51 (s, 2 H),3.72-3.70 (m, 2 H), 3.29 (s, 6 H), 2.45 (s, 3 H).

Example 17-1N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(trifluoromethoxy)quinolin-4-yl]propane-1,3-diamine

4-(4-Chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

A mixture of 2,4-dichloro-6-(trifluoromethoxy)quinoline (250 mg, 0.89mmol), 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (210 mg, 1.06mmol) and n-butanol (2 mL) was heated with stirring in a 5 mL ofmicrowave process vial for 3 hours at 150° C. under microwaveirradiation. The mixture was filtered. The formed solid was collected byfiltration and washed with 10 mL of mixture solution of petroleum etherand ethyl acetate (V/V=10/1) to afford 0.3 g of the product (yield was77%).

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(trifluoromethoxy)quinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 3-1 in Scheme 5 byusing4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and propane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 481, ¹HNMR (400 MHz, CD₃OD) δ ppm 8.16-8.15 (d, J=2.4 Hz, 1 H), 8.09-8.07 (dd,J=5.2, 8.0 Hz, 1 H), 7.94-7.92 (d, J=10 Hz, 1 H), 7.90-7.88 (d, J=8 Hz,1 H), 7.72-7.70 (m, 2 H), 7.58-7.55 (m, 1 H), 6.03 (s, 1 H), 5.34 (s, 2H), 4.55 (s, 2 H), 3.75 (s, 2 H), 3.62-3.59 (t, J=6.8 Hz, 2 H),3.14-3.10 (t, J=8.0 Hz, 2 H), 2.15-2.11 (m, 2 H).

Example 17-2N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(trifluoromethyl)quinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 17-1 in Scheme 6by using4-(4-chloro-6-(trifluoromethyl)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using2,4-dichloro-6-(trifluoromethyl)quinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide) andpropane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 465, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.57 (s, 1 H), 8.09-8.07 (dd, J=6.4, 7.6 Hz, 1 H),7.98-9.97 (d, J=1.6 Hz, 2 H), 7.95-7.87 (d, J=7.2 Hz, 1 H), 7.74-7.70(m, 1 H), 7.60-7.58 (m, 1 H), 6.04 (s, 1 H), 5.34 (s, 2 H), 4.55 (s, 2H), 3.75 (s, 2 H), 3.62-3.59 (t, J=6.8 Hz, 2 H), 3.12-3.08 (t, J=8 Hz, 2H), 2.14-2.10 (t, J=8 Hz, 2 H).

Example 17-3N-[6-(Difluoromethoxy)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 17-1 in Scheme 6by using4-(4-chloro-6-(difluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using2,4-dichloro-6-(difluoromethoxy)quinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide) andpropane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 463, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.02-8.00 (d, J=7.6 Hz, 1 H), 7.98-7.90 (d, J=2 Hz, 1 H),7.84-7.82 (d, J=8.4 Hz, 2 H), 7.68-7.64 (t, J=7.6 Hz, 1 H), 7.54-7.50(m, 1 H), 7.05-6.68 (d, J=73.6 Hz, 2 H), 5.95 (s, 1 H), 5.28 (s, 2 H),4.48 (s, 2 H), 3.68 (s, 2 H), 3.57-3.54 (t, J=6.8 Hz, 2 H), 3.08-3.04(t, J=7.6 Hz, 2 H), 2.11-2.04 (m, 2 H).

Example 17-4N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methoxyquinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 17-1 in Scheme 6by using4-(4-chloro-6-methoxyquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methoxyquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide) andpropane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 427, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.01-7.99 (d, J=8 Hz, 1 H), 7.83-7.81 (d, J=7.2 Hz, 1 H),7.71-7.64 (m, 2 H), 7.52-7.50 (d, J=7.6 Hz, 2 H), 7.30-7.27 (d, J=9.2Hz, 1 H), 5.90 (s, 1 H), 5.25 (s, 2 H), 4.46 (s, 2 H), 3.83 (s, 3 H),3.66 (s, 2 H), 3.56 (s, 2 H), 3.08-3.07 (t, J=7.2 Hz, 2 H), 2.09-2.06(d, J=5.2 Hz, 2 H).

Example 17-5N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 17-1 in Scheme 6by using4-(4-chloro-8-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-8-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide) andpropane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.33 (s, 1 H), 8.08-8.02 (m, 2 H), 7.83-7.86 (d, J=7.2 Hz,1 H), 7.74-7.72 (t, J=8.4 Hz, 1 H), 7.62-7.58 (q, J=7.2 Hz, 2 H),7.34-7.28 (t, J=7.6 Hz, 1 H), 5.98 (s, 2 H), 5.40 (s, 2 H), 4.58 (s, 2H), 3.79 (s, 2 H), 3.64-3.61 (t, J=6.8 Hz, 2 H), 3.09-3.05 (dd, J=7.6,8.4 Hz, 2 H), 2.67 (s, 3 H), 2.10-2.06 (d, J=7.2 Hz, 2 H).

Example 17-6 and 17-7N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-methylquinolin-4-yl]propane-1,3-diamine andN-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-methylquinolin-4-yl]propane-1,3-diamine

A mixture of the title compound prepared in analogy to Example 17-1 byusing propane-1,3-diamine and a mixture of4-(4-chloro-5-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and4-(4-chloro-7-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using a mixture of2,4-dichloro-5-methylquinoline and 2,4-dichloro-7-methylquinoline andpropane-1,3-diamine) was purified by preparative HPLC and SPE to givethe pure title compoundsN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-methylquinolin-4-yl]propane-1,3-diamineandN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-methylquinolin-4-yl]propane-1,3-diamine.

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-methylquinolin-4-yl]propane-1,3-diamine,MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.15-7.98(d, J=7.6 Hz, 1 H), 7.85-7.80 (d, J=7.2 Hz, 1 H), 7.70-7.60 (q, J=6.4Hz, 2 H), 7.55-7.48 (t, J=7.6 Hz, 2 H), 7.21-7.18 (d, J=6.8 Hz, 1 H),5.87 (s, 1 H), 5.26 (s, 2 H), 4.70-4.40 (m, 2 H), 3.71-3.65 (t, J=2.8Hz, 2 H), 3.58-3.50 (t, J=7.2 Hz, 2 H), 3.12-3.05 (t, J=7.6 Hz, 2 H),2.82 (s, 3 H), 2.12-2.03 (m, 2 H).

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-methylquinolin-4-yl]propane-1,3-diamine,MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.10-8.02(m, 1 H), 8.00-7.95 (d, J=8.8 Hz, 1 H), 7.88-7.81 (d, J=7.2 Hz, 1 H),7.70-7.65 (t, J=1.2 Hz, 1 H), 7.57 (s, 1 H), 7.57-7.50 (t, J=16 Hz, 1H), 7.30-7.22 (d, J=8.4 Hz, 1 H), 5.88 (s, 1 H), 5.29 (s, 2 H),4.60-4.40 (m, 2 H), 3.72-3.68 (t, J=1.2 Hz, 2 H), 3.60-3.50 (t, J=2.8Hz, 2 H), 3.10-3.02 (t, J=7.6 Hz, 2 H), 2.45 (s, 3 H), 2.11-2.02 (m, 2H).

Example 17-8N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-fluoroquinolin-4-amine

The title compound was prepared in analogy to Example 17-1 in Scheme 6by using4-(4-chloro-8-fluoroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-8-fluoroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide) andoxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 457, ¹H NMR (400MHz, CD₃OD) δ ppm 8.08 (d, J=7.2 Hz, 1 H), 8.03 (dd, J=2.4, 9.6 Hz, 1H), 7.91-7.84 (m, 2 H), 7.70 (t, J=7.2 Hz, 1 H), 7.57 (t, J=7.6 Hz, 2H), 6.23 (s, 1 H), 5.35 (s, 2 H), 4.63 (d, J=7.2 Hz, 2 H), 4.56-4.51 (m,4 H), 3.92 (s, 2 H), 3.74 (s, 2 H), 3.47 (s, 2 H).

Example 18-1N-[(3-Aminooxetan-3-yl)methyl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

4-(4-Chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide

The title compound was prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 in Scheme 6 by using2,4-dichloro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide.N-[(3-Aminooxetan-3-yl)methyl]-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (2 g, 5.6 mmol), 3-aminomethyloxetan-3-ylamine (572 mg, 5.6mmol), tri(dibenzylideneacetone)dipalladium(0) (256 mg, 0.28 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (348.7 mg, 0.56 mmol),sodium tert-butoxide (1.08 g, 11.2 mmol) and toluene (20 mL) was heatedwith stirring in a 30 mL of sealed tube for 20 hours at 110° C. undernitrogen. The resulting mixture was diluted with ethyl acetate andwashed with water. The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel to give 1.5 g of the product as off-whitefoam.

Example 18-2 and Example 18-3(+)-N-[(3-Aminooxetan-3-yl)methyl]-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amineand(−)-N-[(3-Aminooxetan-3-yl)methyl]-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine

The chiral separation of Example 18-1 (column: IA; flow rate: 15 mL/min;gradient: 50% hexane in ethanol with 0.4% of triethylamine) gives(+)-N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine,MS obsd. (ESI⁺) [(M+H)⁺] 423, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.74 (d,J=7.6 Hz, 1 H), 7.70-7.66 (m, 2 H), 7.48-7.43 (m, 2 H), 7.39 (t, J=7.2Hz, 1 H), 7.29 (dd, J=1.6, 8.4 Hz, 1 H), 6.16 (s, 1 H), 5.21 (d, J=16.0Hz, 1 H), 4.72 (brs, 2 H), 4.62 (d, J=6.8 Hz, 2 H), 4.57 (dd, J=2.4, 6.4Hz, 2 H), 4.43 (brs, 1 H), 3.66 (s, 2 H), 3.42 (m, 2 H), 2.41 (s, 3 H);and(−)-N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine,MS obsd. (ESI⁺) [(M+H)⁺] 423, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.70 (d,J=7.6 Hz, 1 H), 7.65 (m, 2 H), 7.47-7.38 (m, 2 H), 7.33 (t, J=7.2 Hz, 1H), 7.27 (dd, J=1.6, 8.4 Hz, 1 H), 6.12 (s, 1 H), 5.15 (d, J=16.0 Hz, 1H), 4.64 (brs, 2 H), 4.60 (d, J=6.4 Hz, 2 H), 4.55 (dd, J=2.8, 6.4 Hz, 2H), 4.43 (brs, 1 H), 3.63 (s, 2 H), 3.34 (m, 2 H), 2.38 (s, 3 H).

Example 18-4N-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 18-1 in Scheme 6by using4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide in Example 18-1 by using 2,4,6-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and3-aminomethyloxetan-3-ylamine. MS obsd. (ESI⁺) [(M+H)⁺] 443, ¹H NMR (400MHz, CD₃OD) δ ppm 7.94 (d, J=2.02 Hz, 1 H), 7.77 (d, J=7.83 Hz, 1 H),7.71 (d, J=8.59 Hz, 1 H), 7.52-7.34 (m, 4 H), 6.22 (s, 1 H), 5.25 (d,J=15.92 Hz, 2 H), 4.78 (brs, 2 H), 4.65-4.52 (m, 4 H), 3.66 (s, 2 H),3.47-3.38 (m, 2 H).

Example 18-5N-[2-(1-Oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2-difluoropropane-1,3-diamine

The title compound was prepared in analogy to Example 18-1 in Scheme 6by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (prepared in analogy to the one in Example 18-1) and2,2-difluoropropane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 431, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.93 (s, 1 H), 7.81-7.79 (m, 1 H), 7.76-7.74 (d,2 H), 7.62-7.52 (m, 3 H), 6.25 (s, 1 H), 5.45-5.41 (d, 1 H), 5.05 (d, 1H), 4.75 (m, 1 H), 4.45 (m, 1 H), 4.23-4.16 (m, 2 H), 3.72-3.64 (t, 2H), 3.50 (m, 2 H), 2.47 (s, 3 H).

Example 18-6N-[6-Chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2,2-difluoropropane-1,3-diamine

The title compound was prepared in analogy to Example 18-1 in Scheme 6by using4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide in Example 18-1 by using 2,4,6-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and2,2-difluoropropane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 451, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.21 (s, 1 H), 7.86-7.81 (m, 2 H), 7.77-7.74 (m,2 H), 7.58 (m, 2 H), 6.32 (s, 1 H), 5.45 (d, 1 H), 5.05 (d, 1 H), 4.75(m, 1 H), 4.48 (m, 1 H), 4.20 (m, 2 H), 3.68 (t, 2 H), 3.50 (m, 2 H).

Example 18-7N-[6-Chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 18-1 in Scheme 6by using4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide in Example 18-1 by using 2,4,6-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and ethane-1,3-diamine.MS obsd. (ESI⁺) [(M+H)⁺] 401, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.91 (d,J=2.0 Hz, 1 H), 7.76-7.74 (d, J=7.8 Hz, 2 H), 7.53-7.38 (m, 4 H), 6.10(s, 1 H), 5.29-5.25 (d, J=15.2 Hz, 1 H), 4.62 (s, 3 H), 3.57 (m, 4 H),3.19-3.10 (m, 2 H).

Example 18-8N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 18-1 in Scheme 6by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (prepared in analogy to the one in Example 18-1) andoxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR (400MHz, CD₃OD) δ ppm 8.11 (s, 1 H), 7.86-7.75 (m, 3 H), 7.59-7.51 (m, 3 H),7.67 (t, J=3.6 Hz, 1 H), 7.57 (d, J=2.1 Hz, 1 H), 6.22 (s, 1 H), 5.45(d, J=16.4 Hz, 1 H), 5.10 (brs, 1 H), 4.76 (brs, 1 H), 4.60 (m, 4 H),3.94 (d, 2 H), 4.52 (s, 2 H), 3.47 (s, 2 H), 2.46 (s, 3 H).

Example 18-9N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 18-1 in Scheme 6by using4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide in Example 18-1 by using 2,4,6-trichloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) andoxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 457, ¹H NMR (400MHz, CD₃OD) δ ppm 8.31 (d, 1 H), 7.85-7.74 (m, 4 H), 7.60-7.55 (m, 2 H),6.22 (s, 1 H), 5.45 (d, 1 H), 5.11 (d, 1 H), 4.68 (brs, 1 H), 4.65-4.56(m, 4 H), 4.47 (d, 1 H), 3.91 (m, 2 H), 3.55 (m, 2 H), 3.47 (s, 2 H).

Example 18-10N-[6-Methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 18-1 in Scheme 6by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (prepared in analogy to the one in Example 18-1) andethane-1,2-amine. MS obsd. (ESI⁺) [(M+H)⁺] 381, ¹H NMR (400 MHz, CD₃OD)δ ppm 7.89 (s, 1 H), 7.81-7.76 (m, 2 H), 7.73-7.70 (m, 1 H), 7.59-7.49(m, 3 H), 6.02 (s, 1 H), 5.44-5.40 (m, 1 H), 5.04-5.01 (m, 1 H),4.75-4.71 (m, 1 H), 4.48-4.44 (m, 1 H), 3.84-3.81 (t, 2 H), 3.51 (s, 2H), 3.33-3.28 (m, 2 H), 2.45 (s, 3 H).

Example 18-112-{[6-Methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}ethanol

The title compound was prepared in analogy to Example 18-1 in Scheme 6by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (prepared in analogy to the one in Example 18-1) and2-amino-ethanol. MS obsd. (ESI⁺) [(M+H)⁺] 382, ¹H NMR (400 MHz, CD₃OD) δppm 7.92 (s, 1 H), 7.85-7.80 (d, J=8.4 Hz, 1 H), 7.80-7.75 (d, J=7.6 Hz,1 H), 7.75-7.70 (d, J=7.2 Hz, 1 H), 7.61-7.50 (m, 3 H), 6.10 (s, 1 H),5.48-5.39 (m, 1 H), 5.08-4.95 (m, 1 H), 4.80-4.70 (m, 1 H), 4.52-4.42(m, 1 H), 3.88-3.80 (t, J=5.6 Hz, 2 H), 3.65-3.60 (t, J=5.6 Hz, 2 H),3.59-3.40 (m, 2 H), 2.46 (s, 3 H).

Example 19-1trans-4-Amino-1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin-3-ol

tert-Butyl{trans-1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-4-hydroxypyrrolidin-3-yl}carboxylate

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (200 mg, 0.56 mmol, prepared in analogy to the one in Example18-1), tert-butyl [trans-4-hydroxypyrrolidin-3-yl]carbamate (125 mg,0.62 mmol), tris(2-benzylidene acetone) palladium(II) (50 mg, 0.055mmol), 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl (30 mg,0.076 mmol), sodium tert-butoxide (60 mg, 0.625 mmol) and 1,4-dioxane (3mL) in a 2-5 mL of process vial was heated at 120° C. under microwaveirradiation for 2 hours. After being cooled to room temperature, themixture was filtered and washed with ethyl acetate. The filtrate waswashed with brine, dried over sodium sulfate, and concentrated in vacuo.The residue was purified by flash column chromatography (eluting with10% methanol in dichloromethane) to afford 230 mg of the product as awhite solid (yield was 80%).

trans-4-Amino-1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin-3-ol

To a solution of tert-butyl{trans-1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-4-hydroxypyrrolidin-3-yl}carboxylate(230 mg, 0.54 mmol) in dichloromethane (5 mL) was added trifluoroaceticacid (2 mL). After being stirred at room temperature for 3 hours, theresulting mixture was concentrated in vacuo. The residue was purified bypreparative HPLC to afford the pure product as a solid. MS obsd. (ESI⁺)[(M+H)⁺] 423, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.95 (s, 1 H), 7.80-7.76 (d,J=7.2 Hz, 1 H), 7.76-7.70 (m, 2 H), 7.60-7.52 (m, 2 H), 7.52-7.43 (m, 1H), 5.91 (s, 1 H), 5.42-5.30 (m, 1 H), 5.02-4.90 (m, 1 H), 4.80-4.68 (m,1 H), 4.56-4.50 (m, 1 H), 4.50-4.20 (m, 3 H), 3.96-3.88 (m, 1 H),3.86-3.80 (m, 1 H), 3.80-3.70 (m, 1 H), 3.56-3.38 (m, 2 H), 2.43 (s, 3H).

Example 19-2(1R,5S,6S)-3-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-azabicyclo[3.1.0]hexan-6-amine

The title compound was prepared in analogy to Example 19-1 in Scheme 7by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,2-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyl(1R,5S,6S)-3-azabicyclo[3.1.0]hex-6-ylcarbamate. MS obsd. (ESI⁺)[(M+H)⁺] 435, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (dd, J=7.83, 1.01 Hz, 1H), 7.82 (d, J=7.07 Hz, 1 H), 7.71-7.56 (m, 2 H), 7.51-7.39 (m, 2 H),7.27 (dd, J=8.59, 1.77 Hz, 1 H), 6.31 (s, 1 H), 5.15 (s, 2 H), 4.56(brs, 2 H), 3.83 (d, J=9.60 Hz, 2 H), 3.58 (t, J=4.93 Hz, 2 H), 3.38 (d,J=9.60 Hz, 2 H), 2.55 (s, 1 H), 2.40 (s, 3 H), 1.76-1.62 (m, 2 H).

Example 19-3trans-4-Amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol

The title compound was prepared in analogy to Example 19-1 in Scheme 7by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyltrans-(4-hydroxypyrrolidin-3-yl)carbamate. MS obsd. (ESI⁺) [(M+H)⁺] 439,¹H NMR (400 MHz, CD₃OD) δ ppm 7.92-7.83 (m, 2 H), 7.76 (s, 1 H),7.67-7.59 (m, 1 H), 7.47 (t, J=7.45 Hz, 1 H), 7.37 (d, J=8.59 Hz, 1 H),7.23 (dd, J=8.46, 1.39 Hz, 1 H), 6.03 (s, 1 H), 5.18-4.96 (m, 3 H), 4.41(brs, 2 H), 4.04-3.83 (m, 3 H), 3.62 (t, J=4.80 Hz, 2 H), 3.35-3.25 (d,J=9.85 Hz, 2 H), 2.35 (s, 3 H).

Example 19-41-[6-Methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin-3-amine

The title compound was prepared in analogy to Example 19-1 in Scheme 7by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (prepared in analogy to the one in Example 18-1) and tert-butylpyrrolidin-3-ylcarbamate. MS obsd. (ESI⁺) [(M+H)⁺] 407, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.81 (s, 1 H), 7.71 (t, J=8.21 Hz, 2 H), 7.57-7.36 (m, 3H), 7.27 (dd, J=8.59, 1.77 Hz, 1 H), 6.11 (s, 1 H), 5.21 (d, J=16.17 Hz,1 H), 4.76 (d, J=15.92 Hz, 2 H), 4.50 (brs, 1 H), 3.88-3.71 (m, 2 H),3.71-3.53 (m, 2 H), 3.53-3.36 (m, 3 H), 2.40 (s, 3 H), 2.26 (dq,J=12.63, 6.23 Hz, 1 H), 1.98-1.78 (m, 1 H).

Example 19-5trans-1-[6-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-4-fluoropyrrolidin-3-amine

The title compound was prepared in analogy to Example 19-1 in Scheme 7by using4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1) and tert-butyltrans-(4-fluoropyrrolidin-3-yl)carbamate. MS obsd. (ESI⁺) [(M+H)⁺] 461,¹H NMR (400 MHz, CD₃OD) δ ppm 8.03-7.96 (m, 2 H), 7.86 (d, J=7.58 Hz, 1H), 7.63 (td, J=7.45, 1.26 Hz, 1 H), 7.54 (d, J=9.09 Hz, 1 H), 7.46 (td,J=7.71, 1.01 Hz, 1 H), 7.39 (dd, J=9.09, 2.27 Hz, 1 H), 6.25 (s, 1 H),5.14-5.25 (m, 2 H), 5.05 (brs, 1 H), 4.55 (brs, 2 H), 4.18-4.27 (dd,J=12.25, 3.92 Hz, 1 H), 4.01 (dd, J=8.97, 5.18 Hz, 1 H), 3.78-3.55 (m, 4H), 3.40-3.30 (m, 1 H).

Example 19-6trans-4-Amino-1-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin-3-ol

The title compound was prepared in analogy to Example 19-1 in Scheme 7by using4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4,6-trichloro-quinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyl(trans-4-hydroxypyrrolidin-3-yl)carbamate. MS obsd. (ESI⁺) [(M+H)⁺] 459,¹H NMR (400 MHz, CD₃OD) δ ppm 8.03-7.96 (m, 2 H), 7.85 (d, J=7.33 Hz, 1H), 7.66-7.60 (m, 1 H), 7.53 (d, J=9.09 Hz, 1 H), 7.49-7.42 (m, 1 H),7.38 (dd, J=8.97, 2.15 Hz, 1 H), 6.20 (s, 1 H), 5.18 (brs, 2 H),4.70-4.40 (b, 2 H), 4.21 (brs, 1 H), 4.10 (dd, J=10.74, 4.93 Hz, 1 H),3.97 (dd, J=9.60, 5.56 Hz, 1 H), 3.59 (d, J=3.28 Hz, 2 H), 3.54-3.49 (m,1 H), 3.48-3.39 (m, 2 H).

Example 19-7trans-1-[6-Chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-4-fluoropyrrolidin-3-amine

The title compound was prepared in analogy to Example 19-1 in Scheme 7by using4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide in Example 18-1) and tert-butyl(trans-4-fluoropyrrolidin-3-yl)carbamate. MS obsd. (ESI⁺) [(M+H)⁺] 445,¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (d, J=2.27 Hz, 1 H), 7.78-7.68 (m, 2H), 7.55 (dd, J=9.09, 1.52 Hz, 1 H), 7.52-7.42 (m, 2 H), 7.39 (dd,J=9.09, 2.27 Hz, 1 H), 6.28-6.21 (m, 1 H), 5.25 (d, J=15.66 Hz, 1 H),5.10-4.95 (m, 1 H), 4.90-4.54 (m, 2 H), 4.65-4.40 (m, 1 H), 4.30-4.10(m, 1 H), 4.05-3.59 (m, 1 H), 3.55-3.51 (m, 2 H), 3.40-3.35 (m, 3 H).

Example 19-82-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-azabicyclo[2.1.1]hexan-5-amine

The title compound was prepared in analogy to Example 19-1 in Scheme 7by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyl2-azabicyclo[2.1.1]hex-5-ylcarbamate. MS obsd. (ESI⁺) [(M+H)⁺] 435, ¹HNMR (400 MHz, CD₃OD) δ ppm 7.99 (dd, J=7.83, 1.01 Hz, 1 H), 7.86-7.74(m, 2 H), 7.61 (td, J=7.58, 1.26 Hz, 1 H), 7.54-7.39 (m, 2 H), 7.33 (dd,J=8.59, 1.77 Hz, 1 H), 6.43 (s, 1 H), 5.22-5.06 (m, 2 H), 4.38 (d,J=6.32 Hz, 1 H), 3.95 (d, J=8.59 Hz, 1 H), 3.67-3.52 (m, 2 H), 3.42-3.35(m, 1 H), 3.05 (d, J=8.59 Hz, 1 H), 2.91-2.77 (m, 1 H), 2.45 (s, 3 H),1.67 (d, J=7.83 Hz, 1 H), 1.39-1.26 (m, 2 H), 1.19 (d, J=7.83 Hz, 1 H).

Example 20-12-(8-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

tert-Butyl[2-(8-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbamate

A mixture solution of4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (60.0 mg, 0.15 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide),tert-butyl carbamate (45.0 mg, 0.37 mmol),1,1′-bis(diphenylphosphino)ferrocene (11.2 mg, 0.02 mmol),1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (15.0 mg, 0.02mmol), and sodium tert-butoxide (75.0 mg, 0.72 mmol) in 1,4-dioxane (2.0mL) was heated with stirring at 120° C. for 2 hours. After being cooledto room temperature, the reaction mixture was extracted with ethylacetate (100 mL), washed with brine (50 mL×2), dried over anhydroussodium sulfate and concentrated in vacuo to afford 59.9 mg of the crudeproduct as yellow oil. MS obsd. (ESI⁺) [(M+H)⁺] 484.

2-(8-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A mixture solution of tert-butyl[2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbamate(59.0 mg, 0.12 mmol) and trifluoroacetic acid (0.5 mL) indichloromethane (2.0 mL) was stirred at room temperature for 6 hours.Then the reaction mixture was extracted with ethyl acetate (100 mL). Theorganic layer was washed with brine (50 mL×2), dried over anhydroussodium sulfate and then concentrated in vacuo. The residue was purifiedby preparative HPLC to afford 10.2 mg of the product as a white solid(yield was 21.5%). MS obsd. (ESI⁺) [(M+H)⁺] 384, ¹H NMR (400 MHz, CD₃OD)δ ppm 7.72 (d, J=8.34 Hz, 1 H), 7.58 (s, 1 H), 7.50 (d, J=2.78 Hz, 1 H),7.43 (d, J=8.34 Hz, 1 H), 7.29 (dd, J=8.46, 1.89 Hz, 1 H), 7.12 (dd,J=8.34, 2.78 Hz, 1 H), 6.27 (s, 1 H), 5.02 (s, 2 H), 4.47 (brs, 2 H),3.82 (s, 3 H), 3.56 (t, J=4.80 Hz, 2 H), 2.42 (s, 3 H).

Example 20-22-(7-Methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 20-1 in Scheme 7by using4-(4-chloro-6-methylquinolin-2-yl)-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) andtert-butyl carbamate. MS obsd. (ESI⁺) [(M+H)⁺] 384, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.87 (d, J=8.84 Hz, 1 H), 7.59 (s, 1 H), 7.44 (d, J=8.59Hz, 1 H), 7.35 (d, J=2.53 Hz, 1 H), 7.30 (dd, J=8.59, 1.77 Hz, 1 H),6.88 (dd, J=8.72, 2.65 Hz, 1 H), 6.27 (s, 1 H), 5.04 (s, 2 H), 4.46(brs, 2 H), 3.89 (s, 3 H), 3.52 (t, J=4.67 Hz, 2 H), 2.42 (s, 3 H).

Example 20-3[2-(1-Amino-cyclopropyl)-ethyl]-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-amine

The title compound was prepared in analogy to Example 20-1 in Scheme 7by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyl1-(2-aminoethyl)-cyclopropylcarbamate. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹HNMR (400 MHz, CDCl₃) δ ppm 7.95-7.93 (dd, J=1.2, 8.0 Hz, 1 H), 7.59-7.57(d, J=6 Hz, 1 H), 7.42-7.38 (m, 2 H), 7.29-7.25 (m, 1 H), 7.21-7.18 (m,2 H), 6.40 (s, 1 H), 5.79 (s, 1 H), 4.5 (s, 2 H), 3.48 (s, 2 H), 3.35(s, 2 H), 2.44 (s, 3 H), 2.31 (s, 3 H), 1.77-1.74 (d, J=6 Hz, 2 H), 1.54(s, 2 H), 0.56-0.50 (m, 2 H).

Example 21-12-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(morpholin-2-ylmethyl)quinolin-4-amine

tert-Butyl2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-ylamino]-methyl}-morpholine-4-carboxylate

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (682 mg, 1.83 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) in 1,4-dioxane (5mL) was added tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (395mg, 1.83 mmol),1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (146 mg, 0.18mmol), 1,1′-bis(diphenylphosphino)ferrocene (100 mg, 0.18 mmol) andsodium tert-butoxide (350 mg, 3.66 mmol) under Argon protection. Themixture was heated with stirring under microwave irridiation at 120° C.for 1.5 hours. The reaction mixture was concentrated in vacuo and theresidue was purified by preparative HPLC to give 100 mg of the desiredproduct (yield was 10%).

2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(morpholin-2-ylmethyl)quinolin-4-amine

To a solution of tert-butyl2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-ylamino]-methyl}-morpholine-4-carboxylate(100 mg, 0.18 mmol) in ethyl acetate (10 mL) was added a solution ofhydrochloride in ethyl acetate (4 N, 30 mL) in an ice-water bathdropwise. After being stirred at room temperature for 4 hours, themixture was concentrated in vacuo. The residue was purified bypreparative HPLC to afford trifluoroacetic acid salt of the desiredproduct. The trifluoroacetic acid salt was flashed through SPE columnwith methanol to remove the trifluoroacetic acid. The solution wasconcentrated in vacuo and then dried by lyopylization to give 46.94 mgof the desired product (yield was 60%). MS obsd. (ESI⁺) [(M+H)⁺] 453, ¹HNMR (400 MHz, CD₃OD) δ ppm 8.04 (d, J=7.6 Hz, 1 H), 7.90-7.86 (m, 2 H),7.72-7.68 (m, 2 H), 7.56-7.50 (m, 2 H), 6.11 (s, 1 H), 5.29 (s, 2 H),4.55-4.49 (m, 2 H), 4.11-4.01 (m, 2 H), 3.88-3.81 (m, 1 H), 3.71-3.62(m, 4 H), 3.42-3.39 (m, 1 H), 3.33-3.21 (s, 1 H), 3.28-3.01 (m, 2 H),2.45 (s, 3 H).

Example 21-2N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-methylethane-1,2-diamine

The title compound was prepared in analogy to Example 21-1 in Scheme 7by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butylN-[2-(methylamino)ethyl]carbamate. MS obsd. (ESI⁺) [(M+H)⁺] 411, 1H NMR(400 MHz, CD₃OD) δ ppm 7.92 (dd, J=1.6, 7.6 Hz, 1 H), 7.86 (d, J=7.6 Hz,2 H), 7.74 (s, 1 H), 7.61 (t, J=7.6 Hz, 1 H), 7.54 (d, J=8.4 Hz, 1 H),7.40 (t, J=7.6 Hz, 1 H), 7.33 (dd, J=2.0, 8.8 Hz, 1 H), 6.66 (s, 1 H),5.20 (s, 2 H), 4.51 (brs, 2 H), 3.59-3.53 (m, 4 H), 3.24 (t, J=6.4 Hz, 2H), 2.93 (s, 3 H), 2.42 (s, 3 H).

Example 21-3N-(Azetidin-2-ylmethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 21-1 in Scheme 7by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyl2-(aminomethyl)azetidine-1-carboxylate. MS obsd. (ESI⁺) [(M+H)⁺] 423, ¹HNMR (400 MHz, CD₃OD) δ ppm 8.09-8.02 (d, J=4 Hz, 1 H), 7.89 (s, 1 H),7.85-7.79 (d, J=4 Hz, 1 H), 7.72-7.65 (m, 2 H), 7.60-7.50 (m, 2 H), 6.00(s, 1 H), 5.31 (s, 2 H), 4.85-4.75 (m, 1 H), 4.60-4.40 (m, 2 H),4.13-3.95 (m, 3 H), 3.92-3.85 (dd, J=2.8, 12.8 Hz, 1 H), 3.75-3.66 (t,J=2.8 Hz, 2 H), 2.72-2.60 (m, 1 H), 2.52-2.42 (m, 1 H), 2.42 (s, 3 H).

Example 21-42-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 21-1 in Scheme 7by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyl3-aminopyrrolidine-1-carboxylate. MS obsd. (ESI⁺) [(M+H)⁺] 423, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.16 (s, 1 H), 8.12-8.10 (q, J=1.2 Hz, 1 H),7.96-7.94 (d, J=7.6 Hz, 1 H), 7.80-7.74 (m, 2 H), 7.74-7.60 (m, 2 H),6.04 (s, 1 H), 5.39 (s, 2 H), 4.84-4.82 (m, 2 H), 4.58 (s, 2 H),3.81-3.77 (dd, J=6.4, 4.4 Hz, 2 H), 3.62-3.52 (m, 3 H), 2.67-2.30 (m, 1H), 2.61-2.54 (m, 1 H), 2.50 (s, 3 H).

Example 21-5(1-Amino-cyclopropylmethyl)-[2-(5,5-dioxo-5,6,7,9-tetrahydro-5λ⁶-thia-8-aza-benzocyclohepten-8-yl)-6-methyl-quinolin-4-yl]-amine

The title compound was prepared in analogy to Example 21-1 in Scheme 7by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butyl1-(aminomethyl)cyclopropane carbamate. MS obsd. (ESI⁺) [(M+H)⁺] 423, ¹HNMR (400 MHz, CD₃OD) δ ppm 7.98-7.90 (d, J=8 Hz, 1 H), 7.82-7.78 (d,J=7.6 Hz, 1 H), 7.69 (s, 1 H), 7.60-7.52 (t, J=1.2 Hz, 1 H), 7.42-7.36(m, 2 H), 7.29-7.22 (d, J=7.2 Hz, 1 H), 6.00 (s, 1 H), 5.11 (s, 2 H),4.65-4.50 (m, 2 H), 3.60-3.50 (t, J=2.8 Hz, 2 H), 3.40-3.30 (d, J=4.4Hz, 2 H), 2.39 (s, 3 H), 0.70-0.60 (m, 4 H).

Example 22N-(Azetidin-3-yl)-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

tert-Butyl3-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-4-ylamino]-azetidine-1-carboxylate

The title compound was prepared in analogy to tert-butyl2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-ylamino]-methyl}-morpholine-4-carboxylatein Example 21-1 by using4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and tert-butyl 3-aminoazetidine-1-carboxylate.

N-(Azetidin-3-yl)-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

A mixture of tert-butyl3-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-4-ylamino]-azetidine-1-carboxylate(120 mg, 0.2 mmol) and a solution of hydrochloride in 1,4-dioxane (4 N,20 mL) was stirred at room temperature for 16 hours. The resultingmixture was concentrated in vacuo. The residue was purified bypreparative HPLC to afford 50 mg of the desired product (yield was 51%).MS obsd. (ESI⁺) [(M+H)⁺] 429, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.31 (s, 1H), 8.08-8.06 (d, J=8 Hz, 1 H), 7.87-7.80 (m, 2 H), 7.73-7.68 (m, 2 H),7.55-7.53 (m, 1 H), 5.84 (s, 1 H), 5.30 (s, 2 H), 4.99-4.96 (m, 1 H),4.59-4.52 (m, 4 H), 4.32-4.27 (m, 2 H), 3.72 (s, 2 H).

Example 23 6-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-6-azaspiro[3.4]octan-8-amine

tert-Butyl 6-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-6-azaspiro[3.4]octan-8-carbamate

A mixture of tert-butyl 2-oxa-6-azaspiro[3.4]oct-8-ylcarbamate (459 mg,2.0 mmol),4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (500 mg, 1.34 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide),tri(dibenzylideneacetone)dipalladium(0) (61.3 mg, 0.067 mmol),2′-(dicyclohexylphosphino)-N,N-dimethyl[1,1′-biphenyl]-2-amine (52.7 mg,0.134 mmol), sodium tert-butoxide (192.2 mg, 2.0 mmol) and 1,4-dioxane(6 mL) was heated with stirring in a 20 mL of microwave process vial for3 hours at 100° C. The mixture was diluted with ethyl acetate and washedwith water. The organic layer was dried over sodium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel to give 700 mg of the product as a white solid, which wasused for next step without further purification.

6-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-6-azaspiro[3.4]octan-8-amine

To a solution of tert-butyl6-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-6-azaspiro[3.4]octan-8-carbamate(700 mg, 1.24 mmol) in dichloromethane (10 mL) was added trifluoroaceticacid (5 mL) at 0° C. The resulting mixture was stirred at roomtemperature for further 30 minutes. The reaction was quenched with asaturated aqueous solution of sodium carbonate, and the mixture wasextracted with dichloromethane. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bypreparative HPLC to give 80 mg of the product as a white solid. MS obsd.(ESI⁺) [(M+H)⁺] 465, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.97 (d, J=7.6 Hz, 1H), 7.83 (d, J=7.6 Hz, 1 H), 7.79 (s, 1 H), 7.63 (m, 1 H), 7.52 (d,J=8.4 Hz, 1 H), 7.44 (m, 1 H), 7.35 (m, 1 H), 6.10 (s, 1 H), 5.17 (s, 2H), 4.95 (d, J=6.8 Hz, 1 H), 4.68-4.62 (m, 3 H), 4.50 (brs, 2 H), 4.10(d, J=8.8 Hz, 1 H), 3.91-3.81 (m, 3 H), 3.60 (m, 2 H), 3.45 (m 1 H),2.41 (s, 3 H).

Example 24trans-4-Amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]pyrrolidin-3-ol

tert-Butyltrans-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]-3-hydroxypyrrolidin-4-carbamate

To a solution of-(4-chloro-1,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (300 mg, 0.84 mmol, prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using2,3,4,5-tetrahydro-1,4-benzothiazepine and2,4-dichloro-1,6-naphthyridine) in 1,4-dioxane (5 mL) was addedtert-butyl (trans-4-hydroxypyrrolidin-3-yl)carbamate (204 mg, 1.02mmol), tri(dibenzylideneacetone)dipalladium(0) (39 mg, 0.042 mmol),(2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (24 mg, 0.063mmol) and sodium tert-butoxide (114 mg, 1.17 mmol) under Ar protection.The reaction mixture was heated with stirring in a 10 mL of microwaveprocess vial for 2 hours at 120° C. The reaction mixture wasconcentrated in vacuo. The residue was purified by preparative HPLC togive 45 mg of the desired product (yield was 10%).

trans-4-Amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]pyrrolidin-3-ol

To a solution of tert-butyltrans-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]-3-hydroxypyrrolidin-4-carbamate(45 mg, 0.08 mmol) in ethyl acetate (10 mL) was added a solution ofhydrochloride in ethyl acetate (4 N, 30 mL) in an ice-water bathdropwise. After being stirred at room temperature for 4 hours, themixture was concentrated in vacuo. The residue was purified bypreparative HPLC to give the trifluoroacetic acid salt of the desiredproduct. The trifluoroacetic acid salt was flashed through SPE columnwith methanol. The solution was concentrated in vacuo and dried bylyopylization to afford 10.9 mg of the desired product (yield was 30%).MS obsd. (ESI⁺) [(M+H)⁺] 426, ¹H NMR (400 MHz, CD₃OD) δ ppm 9.23 (s, 1H), 8.23 (d, J=7.2 Hz, 1 H), 7.99 (d, J=7.6 Hz, 1 H), 7.87 (d, J=7.2 Hz,1 H), 7.66-7.64 (m, 2 H), 7.48 (t, J=7.6 Hz, 1 H), 6.16 (s, 1 H), 5.25(s, 2 H), 4.70-4.40 (m, 3 H), 4.26-4.18 (m, 2 H), 3.87-3.85 (m, 1 H),3.81-3.78 (m, 1 H), 3.71-3.68 (m, 1 H), 3.55 (t, J=4.8 Hz, 2 H).

Example 251-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (0.3 g, 0.8 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide) and tert-butylpyrrolidine-3-carbamate (0.3 g, 1.6 mmol) was heated with stirring in a10 mL of microwave process vial for 1 hour at 140° C. The resultingmixture was purified by preparative HPLC and SPE. After SPE separation,the eluent was concentrated in vacuo to remove the organic solution. Theresidue was dried by lyophylization to afford 82.9 mg of the desiredproduct (yield was 25%). MS obsd. (ESI⁺) [(M+H)⁺] 423, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.09-8.08 (dd, J=4.0, 8.0 Hz, 1 H), 8.02 (s, 1 H),7.85-7.83 (q, J=7.6 Hz, 1 H), 7.77-7.70 (m, 2 H), 7.61-7.56 (m, 2 H),5.90 (s, 1 H), 5.30 (s, 2 H), 4.52 (s, 2 H), 4.30-4.26 (m, 1 H),4.17-4.11 (m, 2 H) 3.99-3.96 (m, 2 H), 3.74 (s, 2 H), 2.57-2.52 (m, 1H), 2.47 (s, 3 H), 2.35-2.28 (m, 1 H).

Example 26-1N-(Azetidin-3-yl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

tert-Butyl3-[1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-ylamino]-azetidine-1-carboxylate

A mixture of8-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (900 mg, 2.16 mmol, prepared in analogy to the one inExample 2-1) and tert-butyl 3-aminoazetidine-1-carboxylate (1.86 g,10.77 mmol) was heated with stirring in a 10 mL of microwave processvial for 1 hour at 150° C. The resulting mixture was purified bypreparative HPLC to afford 110 mg of the desired product (yield was 7%).

N-(Azetidin-3-yl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

To a solution of tert-butyl3-[1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-ylamino]-azetidine-1-carboxylate(110 mg, 0.22 mmol) in ethyl acetate (10 mL) was added a solution ofhydrochloride in ethyl acetate (4 N, 30 mL) in an ice-water bathdropwise. After being stirred at room temperature for 4 hours, themixture was concentrated in vacuo. The residue was purified bypreparative HPLC to give the trifluoroacetic acid salt of the desiredproduct. The trifluoroacetic acid salt was flashed through SPE columnwith methanol. The solution was concentrated in vacuo and dried bylyopylization to afford 29 mg of the desired product (yield was 33%). MSobsd. (ESI⁺) [(M+H)⁺] 409, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.09 (d, J=7.2Hz, 1 H), 8.02 (s, 1 H), 7.84-7.82 (m, 1 H), 7.76-7.72 (m, 2 H),7.65-7.60 (m, 2 H), 5.79 (s, 1 H), 5.33 (s, 2 H), 4.96-4.92 (m, 1 H),4.55-4.50 (m, 4 H), 4.31-4.28 (m, 2 H), 3.76 (s, 2 H), 2.49 (s, 3 H).

Example 26-21-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]azetidin-3-amine

The title compound was prepared in analogy to Example 26-1 in Scheme 7by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andtert-butyl azetidin-3-ylcarbamate. MS obsd. (ESI⁺) [(M+H)⁺] 409, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.03-8.00 (d, J=7.6 Hz, 1 H), 7.87 (s, 1 H),7.80-7.78 (d, J=7.6 Hz, 1 H), 7.67-7.62 (m, 2 H), 7.56-7.50 (m, 2 H),6.00 (s, 1 H), 5.29 (s, 2 H), 4.47 (s, 2 H), 3.97-3.89 (m, 3 H),3.82-3.69 (m, 4 H), 2.40 (s, 3 H).

Example 27N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]prolinamide

tert-Butyl2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbamoyl}pyrrolidine-1-carboxylate

To a solution of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (0.60 g, 1.6 mmol, prepared in analogy to the one in Example2-1), tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (0.34 g, 1.6mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride(0.13 g, 0.16 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.089 g, 0.16mmol) and sodium tert-butoxide (0.307 g, 3.2 mmol) in 1,4-dioxane (25mL) was heated with stirring for 1.5 hours at 120° C. under microwaveirradiation. The reaction mixture was filtered and concentrated invacuo. The residue was purified by preparative TLC (eluting with 50%ethyl acetate in petroleum ether, V/V=1:1) to give 250 mg of the desiredproduct (yield was 29%).

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]prolinamide

To a solution of tert-butyl2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbamoyl}pyrrolidine-1-carboxylate(250 mg, 0.44 mmol) in ethyl acetate (5 mL) was added a solution ofhydrochloride in ethyl acetate (4 N, 20 mL) dropwise in an ice-waterbath. After being stirred at room temperature for 14 hours, the reactionmixture was concentrated in vacuo. The residue was purified bypreparative TLC to give 104.8 mg of the desired product (yield was 48%).MS obsd. (ESI⁺) [(M+H)⁺] 451, ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (s, 1H), 7.88-7.84 (m, 2 H), 7.63-7.59 (m, 1 H), 7.54 (s, 1 H) 7.49-7.44 (m,2 H), 7.39-7.37 (m, 2 H), 7.00 (s, 1 H), 5.04 (s, 2 H), 4.40 (s, 2 H),4.16-4.12 (t, J=5.2 Hz, 1 H), 3.64 (s, 2 H) 3.15-3.01 (m, 3 H), 2.39 (s,3 H), 2.23-2.20 (m, 1 H), 1.95-1.90 (m, 1 H), 1.80-1.75 (m, 1 H).

Example 28-12-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-trans-(4-fluoropyrrolidin-3-yl)-6-methylquinolin-4-amine

Benzyltrans-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-4-fluoropyrrolidine-1-carboxylate

The title compound was prepared in analogy to Example 8-1 in Scheme 7 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and benzyltrans-3-amino-4-fluoropyrrolidine-1-carboxylare.

2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-(trans-4-fluoropyrrolidin-3-yl)-6-methylquinolin-4-amine

To a suspension of benzyltrans-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-4-fluoropyrrolidine-1-carboxylate(320 mg, 0.557 mmol) in methanol (5 mL) was added an aqueous solution ofpotassium hydroxide (40%, 5 mL). The suspension was heated under refluxfor 30 minutes. The organic solvent was removed by concentration invacuo. The residue was purified by preparative HPLC to afford the pureproduct as a solid. MS obsd. (ESI⁺) [(M+H)⁺] 441, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.01 (d, J=6.57 Hz, 1 H), 7.85 (d, J=7.33 Hz, 1 H), 7.67(s, 1 H), 7.63 (t, J=7.07 Hz, 1 H), 7.53-7.40 (m, 2 H), 7.30 (d, J=8.84Hz, 1 H), 6.18 (s, 1 H), 5.15 (s, 2 H), 5.10 (brs, 1 H), 4.97 (brs, 1H), 3.60 (dd, J=12.00, 6.44 Hz, 3 H), 3.28 (brs, 1 H), 3.23 (dd, J=8.84,5.31 Hz, 1 H), 3.18-3.12 (m, 1 H), 3.04 (dd, J=12.00, 4.67 Hz, 1 H),2.42 (s, 3 H).

Example 28-2trans-4-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}pyrrolidin-3-ol

The title compound was prepared in analogy to Example 28-1 in Scheme 8by using 4-(4-bromoquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1) and benzyltrans-3-amino-4-hydroxypyrrolidine-1-carboxylate. MS obsd. (ESI⁺)[(M+H)⁺] 439, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.29-8.22 (d, J=7.6 Hz, 1H), 8.12-8.08 (d, J=1.2 Hz, 1 H), 7.98-7.92 (d, J=7.6 Hz, 1 H),7.88-7.82 (d, J=0.8 Hz, 1 H), 7.80-7.71 (m, 2 H), 7.62-7.58 (t, J=1.2Hz, 1 H), 7.50-7.42 (t, J=6.8 Hz, 1 H), 6.20 (s, 1 H), 5.45-5.30 (q,J=7.2 Hz, 2 H), 4.62-4.52 (m, 2 H), 4.52-4.45 (m, 2 H), 4.05-3.95 (q,J=4.4 Hz, 1 H), 3.80-3.75 (t, J=2.8 Hz, 2 H), 3.75-3.68 (m, 1 H),3.62-3.55 (dd, J=2.8, 12.8 Hz, 1 H), 3.48-3.40 (d, J=7.6 Hz, 1 H).

Example 28-3trans-4-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}pyrrolidin-3-ol

The title compound was prepared in analogy to Example 28-1 in Scheme 8by using4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and benzyl(3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate. MS obsd. (ESI⁺)[(M+H)⁺] 439, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.13-8.10 (d, J=7.6 Hz, 1H), 8.06 (s, 1 H), 7.95-7.90 (d, J=7.2 Hz, 1 H), 7.78-7.70 (m, 2 H),7.65-7.58 (m, 2 H), 6.16 (s, 1 H), 5.3 (q, J=1.2 Hz, 2 H), 4.65-4.40 (m,2 H), 4.50-4.40 (m, 2 H), 4.12-3.95 (m, 1 H), 3.80-3.68 (m, 3 H),3.60-3.50 (m, 1 H), 3.48-3.40 (d, J=7.2 Hz, 1 H), 2.47 (s, 3 H).

Example 28-4cis-4-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}pyrrolidin-3-ol

The title compound was prepared in analogy to Example 28-1 in Scheme 8by using4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) and benzylcis-3-amino-4-hydroxypyrrolidine-1-carboxylate. MS obsd. (ESI⁺) [(M+H)⁺]439, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.12-8.07 (m, 2 H), 7.98-7.90 (d,J=7.6 Hz, 1 H), 7.78-7.70 (m, 2 H), 7.63-7.58 (m, 2 H), 6.16 (s, 1 H),5.41-5.28 (m, 2 H), 4.61-4.50 (m, 2 H), 4.48 (s, 2 H), 4.02-3.93 (q, J=6Hz, 1 H), 3.78-3.68 (m, 3 H), 3.60-3.50 (dd, J=2.8, 12.8 Hz, 1 H),3.48-3.40 (d, J=3.6 Hz, 1 H), 2.46 (s, 3 H).

Example 28-5N-[trans-4-Fluoropyrrolidin-3-yl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 28-1 in Scheme 8by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (prepared in analogy to the one in Example 18-1) and benzyltrans-3-amino-4-fluoropyrrolidine-1-carboxylare. MS obsd. (ESI⁺)[(M+H)⁺] 425, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.75 (m, 3 H), 7.50 (m, 3H), 7.35 (d, J=8.4 Hz, 1 H), 6.16 (brs, 1 H), 5.28-4.97 (m, 3 H), 4.61(s, 1 H), 4.28 (m, 1 H), 3.64 (m, 1 H), 3.47 (s, 2 H), 3.30-3.08 (m, 2H), 2.43 (s, 3 H).

Example 294-[(3-Aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-ol

4-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-6-ol

A mixture of4-(4-chloro-6-methoxyquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (5.0 g, 12.85 mmol, prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4-dichloro-6-methoxyquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and hydrobromic acid (350 mL,48%) was refluxed for 2 days. The resulting mixture was basified with anaqueous solution of sodium hydroxide (4 N) to about pH 9 and extractedwith ethyl acetate (250 mL×3). The combined organic layers were driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby preparative HPLC to afford 3.0 g of the desired product (yield was62.2%).

4-[(3-Aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-ol

A mixture of4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-6-ol(400 mg, 1.067 mmol) and propane-1,3-diamine (158 mg, 2.134 mmol) washeated with stirring for 1.5 hours at 150° C. under microwaveirradiation. The reacting mixture was purified by preparative HPLC andSPE to give 118.8 mg of the desired product (yield was 27%). MS obsd.(ESI⁺)[(M+H)⁺] 413, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.10-8.05 (d, J=7.6Hz, 1 H), 7.85-7.80 (d, J=8 Hz, 1 H), 7.71-7.62 (m, 2 H), 7.60-7.52 (t,J=7.2 Hz, 1 H), 7.40-7.35 (m, 1 H), 7.26-7.20 (dd, J=2.8 Hz, 12.8 Hz, 1H), 5.91 (s, 1 H), 5.27 (s, 2 H), 4.52-4.42 (m, 2 H), 3.72-3.68 (t,J=2.8 Hz, 2 H), 3.60-3.52 (t, J=6.8 Hz, 2 H), 3.10-3.02 (t, J=7.2 Hz, 2H), 2.10-2.00 (m, 2 H);

Example 30-12-({4-[(3-Aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}oxy)ethanol

2-[4-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-6-yloxy]-ethanol

A mixture of4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-6-ol(250 mg, 0.67 mmol, prepared in analogy to the one in Example 29),2-bromo-ethanol (166.7 mg, 1.33 mmol), and potassium carbonate (277 mg,2.01 mmol) in acetone (30 mL) was stirred at room temperature overnightand then refluxed for 12 hours. The reacting mixture was filtered andconcentrated in vacuo. The residue was purified by preparative TLC toafford 230 mg of the desired product (yield was 82%).

2-({4-[(3-Aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}oxy)ethanol

A mixture of2-{[4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]oxy}ethanol (250 mg, 0.6 mmol) andpropane-1,3-diamine (88.8 mg, 1.2 mmol) was heated for 1.5 hours at 150°C. under microwave irradiation. The reacting mixture was purified bypreparative HPLC and SPE to afford 98.2 mg of the desired product (yieldwas 35.8%). MS obsd. (ESI⁺) [(M+H)⁺] 457, ¹H NMR (400 MHz, CD₃OD) δ ppm8.10-8.02 (d, J=8 Hz, 1 H), 7.88-7.80 (d, J=7.6 Hz, 1 H), 7.77-7.68 (q,J=9.6 Hz, 2 H), 7.60-7.50 (m, 2 H), 7.42-7.38 (m, 1 H), 5.94 (s, 1 H),5.29 (s, 2 H), 4.55-4.42 (m, 2 H), 4.18-4.10 (t, J=4.4 Hz, 2 H),3.90-3.85 (t, J=4.4 Hz, 2 H), 3.76-3.68 (t, J=4.4 Hz, 2 H), 3.62-3.55(t, J=6.8 Hz, 2 H), 3.12-3.05 (t, J=7.6 Hz, 2 H), 2.15-2.00 (m, 2 H).

Example 30-2N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(2-methoxyethoxy)quinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 30-1 by using4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-ol(prepared in analogy to the one in Example 29), 1-bromo-2-methoxyethaneand propane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 471, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.10-8.05 (d, J=8 Hz, 1 H), 7.90-7.83 (d, J=7.6 Hz, 1 H),7.77-7.68 (q, J=9.2 Hz, 2 H), 7.60-7.52 (m, 2 H), 7.42-7.36 (m, 1 H),5.95 (s, 1 H), 5.30 (s, 2 H), 4.56-4.45 (m, 2 H), 4.22-4.18 (t, J=2.8Hz, 2 H), 3.80-3.75 (t, J=2.8 Hz, 2 H), 3.75-3.70 (t, J=4.4 Hz, 2 H),3.65-3.58 (t, J=6.8 Hz, 2 H), 3.42 (s, 3 H), 3.15-3.09 (t, J=7.6 Hz, 2H), 2.16-2.05 (m, 2 H).

Example 31N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(pyridin-2-yloxy)quinolin-4-yl]propane-1,3-diamine

8-[4-Chloro-6-(pyridin-2-yloxy)-quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

A mixture of4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-ol(400 mg, 1.067 mmol), 2-bromo-pyridine (337 mg, 2.134 mmol, prepared inanalogy to the one in Example 29), copper(I) iodide (40 mg, 0.107 mmol),N,N′-dimethyl-cyclohexane-1,2-diamine (2.0 mg, 0.107 mmol) and potassiumcarbonate (250 mg, 2.134 mmol) in 1,2-dimethoxyethane (5 mL) was heatedat 120° C. for 1 hour under microwave irridiation. The resulting mixturewas filtered and concentrated in vacuo. The residue was purified bypreparative HPLC to afford 300 mg of the desired product (yield was62.2%).

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(pyridin-2-yloxy)quinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 30-1 in Scheme 9by using8-[4-chloro-6-(pyridin-2-yloxy)-quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and propane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 490, ¹HNMR (400 MHz, CD₃OD) δ ppm 8.10-8.02 (m, 2 H), 7.92-7.90 (m, 1 H),7.88-7.80 (m, 3 H), 7.71-7.65 (t, J=7.2 Hz, 1 H), 7.60-7.48 (m, 2 H),7.15-7.09 (t, J=0.8 Hz, 1 H), 7.06-7.00 (d, J=8.4 Hz, 1 H), 5.96 (s, 1H), 5.31 (s, 2 H), 4.55-4.42 (m, 2 H), 3.78-3.69 (t, J=2.8 Hz, 2 H),3.60-3.50 (t, J=6.8 Hz, 2 H), 3.08-3.00 (t, J=7.6 Hz, 2 H), 2.10-2.00(m, 2 H).

Example 32-13-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (200.0 mg, 0.54 mmol, prepared in analogy to the one inExample 2-1) and 1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.5 mL,3.8 mmol) was heated with stirring at 160° C. for 16 hours. After beingcooled to room temperature, the resulting reaction mixture was dilutedwith methanol (2.0 mL). Concentrated hydrochloric acid (12.0 N, 0.5 mL)was introduced to the above mixture. The resulting mixture was stirredat room temperature for 1 hour, and then extracted with ethyl acetate(100 mL). The organic layer was washed with brine (50 mL×2), dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by preparative HPLC to afford 69.2 mg of the product as a whitesolid (yield was 30%). MS obsd. (ESI⁺) [(M+H)⁺] 428, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.98 (dd, J=7.83, 1.26 Hz, 1 H), 7.89 (d, J=7.33 Hz, 1 H),7.63 (td, J=7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50-7.35 (m, 2 H), 7.29(dd, J=8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2H), 4.04-3.89 (m, 1 H), 3.69 (d, J=5.56 Hz, 2 H), 3.64-3.49 (m, 4 H),2.41 (s, 3 H).

Example 32-23-{[6-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}propane-1,2-diol

The title compound was prepared in analogy to Example 32-1 in Scheme 10by using4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4,6-triochloroquinoline and2,3,4,5-tetrahydro-1,4-benzothiazepine) and1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine. MS obsd. (ESI⁺) [(M+H)⁺]448. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.23 (d, J=2.02 Hz, 1 H), 8.12 (dd,J=7.83, 1.01 Hz, 1 H), 7.97 (d, J=6.82 Hz, 1 H), 7.87-7.80 (m, 1 H),7.80-7.68 (m, 2 H), 7.66-7.54 (m, 1 H), 6.30 (s, 1 H), 5.32 (s, 2 H),4.56 (brs, 2 H), 4.04-3.83 (m, 1 H), 3.83-3.60 (m, 5 H), 3.54 (dd,J=14.27, 7.20 Hz, 1 H).

Example 32-33-{[2-(8-Chloro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol

The title compound was prepared in analogy to Example 32-1 in Scheme 10by using4-(4-chloro-6-methylquinolin-2-yl)-8-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1 by using 2,4-dichloro-6-methylquinoline and8-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine) and1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine. MS obsd. (ESI⁺) [(M+H)⁺]462. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.04 (d, J=2.27 Hz, 1 H), 7.94 (d,J=10.36 Hz, 2 H), 7.67-7.82 (m, 2 H), 7.61 (dd, J=8.59, 1.26 Hz, 1 H),6.21 (s, 1 H), 5.28 (s, 2 H), 4.54 (brs, 2 H), 4.02-3.90 (m, 1 H), 3.80(brs, 2 H), 3.76-3.61 (m, 3 H), 3.54 (dd, J=14.15, 7.33 Hz, 1 H), 2.50(s, 3 H).

Example 32-43-{[6-Methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}propane-1,2-diol

The title compound was prepared in analogy to Example 32-1 in Scheme 5by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (prepared in analogy to the one in Example 18-1) and1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine. MS obsd. (ESI⁺) [(M+H)⁺]412, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.78 (d, J=7.33 Hz, 1 H), 7.74 (dd,J=7.58, 1.26 Hz, 1 H), 7.62 (s, 1 H), 7.55-7.39 (m, 3 H), 7.33 (dd,J=8.34, 1.52 Hz, 1 H), 6.13 (s, 1 H), 5.24 (dd, J=16.04, 2.91 Hz, 2 H),4.82 (d, J=7.58 Hz, 1 H), 4.76 (d, J=14.15 Hz, 2 H), 4.06-3.83 (m, 1 H),3.75-3.63 (m, 2 H), 3.63-3.52 (m, 1 H), 3.45 (d, J=3.79 Hz, 2 H), 3.37(td, J=6.88, 4.42 Hz, 1 H), 2.43 (s, 3 H).

Example 32-53-{[6-Methyl-2-(5-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}propane-1,2-diol

4-(4-Chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine

A mixture of 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.0 g,5.58 mmol) and 2,4-dichloro-6-methylquinoline (1.7 g, 8.02 mmol) washeated with stirring in a 2 mL of microwave process vial for 5 hours at170° C. under microwave irradiation. The solvent was removed byconcentration in vacuo. The residue was purified by flash columnchromatography to give 560 mg of the mixture of5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and4-(4-chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine.

4-(4-Chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

To a solution of the above mixture of5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and4-(4-chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine(427 mg) in dichloromethane was added a solution of 3-chloroperbenzoicacid (693 mg, 3.01 mmol) in dichloromethane in an ice bath. After beingstirred for 1.5 hours in an ice bath, the reaction mixture was washedwith a saturated aqueous solution of sodium bicarbonate and brine. Theorganic layer was dried over anhydrous sodium sulfate, and concentratedin vacuo. The residue was purified by flash column chromatography togive 130 mg of the product.

3-{[6-Methyl-2-(5-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}propane-1,2-diol

The title compound was prepared in analogy to Example 32-1 in Scheme 10by using4-(4-chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and 1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine. MS obsd.(ESI⁺) [(M+H)⁺] 453, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.03 (dd, J=7.96,1.39 Hz, 1 H), 7.90 (d, J=6.57 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.46 (ddd,J=8.15, 6.63, 1.64 Hz, 2 H), 7.33 (dd, J=8.59, 1.77 Hz, 1 H), 6.15 (s, 1H), 5.86 (d, J=6.82 Hz, 1 H), 4.64-4.53 (m, 4 H), 3.70 (d, J=8.59 Hz, 1H), 3.62-3.58 (m, 2 H), 3.57-3.49 (m, 1 H), 2.43 (s, 3 H), 2.00 (d,J=7.07 Hz, 3 H).

Example 33-1N-[(3-Aminooxetan-3-yl)methyl]-2-(7-morpholin-4-yl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

N-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-6-methyl-2-[7-(morpholin-4-yl)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine

A mixture ofN-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-methyl-2-[7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine(100 mg, 0.16 mmol, prepared in analogy toN-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-aminein Example 1-1 by using 2,4-dichloro-6-methylquinoline,7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine and3-(aminomethyl)-N,N-dibenzyloxetan-3-amine) and morpholine (0.5 mL) washeated with stirring in a sealed 2 mL of microwave process via for 3hours at 120° C. under microwave irradiation. The resulting mixture wasconcentrated in vacuo to afford 111 mg of the crude product which wasused in next step without purification. MS obsd. (ESI⁺) [(M+H)⁺] 704.

N-[(3-Aminooxetan-3-yl)methyl]-2-[(7-morpholin-4-yl)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]-6-methylquinolin-4-amine

A mixture ofN-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-methyl-2-[7-(morpholin-4-yl)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine(100 mg, 0.14 mmol), 10% palladium hydroxide on active carbon (100 mg)and trifluoroacetic acid (0.5 mL) in methanol (20 mL) was stirred for 12hours under hydrogen (1 bar). Then the mixture was basified with asaturated aqueous solution of sodium bicarbonate, and extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified bypreparative HPLC to afford 30 mg of the product (yield was 40%). MSobsd. (ESI⁺) [(M+H)⁺] 524, ¹HNMR ((400 MHz, CD₃OD) δ ppm 7.72-7.60 (m, 2H), 7.56 (d, J=2.27 Hz, 1 H), 7.33 (d, J=8.34 Hz, 1 H), 7.25 (dd,J=8.46, 1.39 Hz, 1 H), 6.85 (dd, J=8.84, 2.53 Hz, 1 H), 6.30-6.03 (m, 2H), 5.00 (brs, 2 H), 4.53-4.31 (m, 4 H), 3.86-3.68 (m, 4 H), 3.51 (d,J=14.40 Hz, 4 H), 3.33-3.19 (m, 6 H), 2.41 (brs, 1 H), 2.37 (s, 3 H).

Example 33-2N-[(3-Aminooxetan-3-yl)methyl]-2-{1,1-dioxido-7-[4-(propan-2-yl)piperazin-1-yl]-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl}-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 33-1 in Scheme 11by usingN-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-methyl-2-[7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine(prepared in analogy to the one in Example 33-1) and4-(propan-2-yl)piperazine. MS obsd. (ESI⁺) [(M+H)⁺] 565, ¹HNMR ((400MHz, CD₃OD) δ ppm 7.82-7.67 (m, 2 H), 7.58 (d, J=8.59 Hz, 1 H), 7.46 (d,J=2.53 Hz, 1 H), 7.35 (dd, J=8.59, 1.52 Hz, 1 H), 6.72 (dd, J=8.97, 2.15Hz, 1 H), 6.14 (s, 1 H), 5.11 (brs, 2 H), 4.62 (q, J=6.57 Hz, 4 H),4.56-4.36 (m, 2 H), 3.82-3.65 (m, 2 H), 3.54 (brs, 2 H), 3.50-3.39 (m, 4H), 2.90-2.88 (m, 1 H), 2.88-2.72 (m, 4 H), 2.50-2.40 (m, 3 H),1.26-1.11 (m, 6 H).

Example 343-{[4-(4-Aminoquinolin-2-yl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl]oxy}propan-1-ol

4-(4-Chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol1,1-dioxide

To a stirred solution of4-(4-chloroquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (2.0 g, 5.15 mmol, prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 2-1) in dry methylene chloride (70.0 mL) wasadded a solution of boron tribromide (2.5 ml, 25.7 mmol) in drymethylene chloride (10 ml) at 0° C. After being stirred at 0° C. for 1hour, the reaction was quenched by addition of a saturated aqueoussodium bicarbonate solution (30 mL). The mixture was extracted withethyl acetate (100 mL×2). The combined organic layers were washed with asaturated aqueous sodium bicarbonate solution (20 mL×3) and brine (20mL×3), dried over anhydrous sodium sulfate and concentrated in vacuo toafford 1.95 g of the crude product as a white solid. MS obsd. (ESI⁺)[(M+H)⁺] 375.

3-{[4-(4-Chloroquinolin-2-yl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl]oxy}propan-1-ol

A mixture of4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol1,1-dioxide (374.0 mg, 1.0 mmol), 3-bromo-propan-1-ol (0.37 mL, 3.0mmol) and potassium carbonate (415.0 mg, 3.0 mmol) inN,N-dimethylformamide (1.5 mL) was heated with stirring at 70° C. for 2hours. After being cooled to room temperature, the resulting mixture wasextracted with ethyl acetate (150 mL×2). The combined organic layerswere washed with water (50 mL×2) and a saturated aqueous ammoniumchloride solution (50 mL×2), dried over anhydrous sodium sulfate andthen concentrated in vacuo to afford 421.6 mg of the crude product as ayellow oil which was used for next step without further purification. MSobsd. (ESI⁺) [(M+H)⁺] 433.

tert-Butyl{2-[8-(3-hydroxypropoxy)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-yl}carbamate

A mixture solution of3-{[4-(4-chloroquinolin-2-yl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl]oxy}propan-1-ol(300.0 mg, 0.70 mmol), tert-butyl carbamate (175.0 mg, 1.5 mmol),1,1′-bis(diphenylphosphino)ferrocene (70.0 mg, 0.113 mmol),1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (70.0 mg,0.075 mmol) and sodium tert-butoxide (232.0 mg, 2.25 mmol) in1,4-dioxane (2.0 mL) was heated with stirring at 120° C. for 2 hoursunder microwave irridiation. After being cooled to room temperature, thereaction mixture was extracted with ethyl acetate (100 mL). The organiclayer was washed with brine (50 mL×2), dried over anhydrous sodiumsulfate and concentrated in vacuo to afford 359.1 mg of the crudeproduct as yellow oil which was used for next step without furtherpurification. MS obsd. (ESI⁺) [(M+H)⁺] 514.

3-{[4-(4-Aminoquinolin-2-yl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl]oxy}propan-1-ol

A mixture solution of tert-butyl{2-[8-(3-hydroxypropoxy)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-yl}carbamate(359.1 mg, the crude product of the above step) and trifluoroacetic acid(1.0 mL) in dichloromethane (2.0 mL) was stirred at room temperature for6 hours. The reaction mixture was diluted with water (10 mL) andextracted with ethyl acetate (100 mL). The organic layer was washed withbrine (50 mL×2), dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified by preparative HPLC to afford 14.2 mg ofthe desired product as a white solid (yield was 4.9%). MS obsd. (ESI⁺)[(M+H)⁺] 414, ¹HNMR ((400 MHz, CD₃OD) δ ppm 7.82-7.67 (m, 2 H),7.54-7.48 (m, 2 H), 7.48-7.39 (m, 1 H), 7.19-7.06 (m, 2 H), 6.30 (s, 1H), 5.04 (s, 2 H), 4.78-4.34 (m, 2 H), 4.11 (t, J=6.32 Hz, 2 H), 3.71(t, J=6.19 Hz, 2 H), 3.62-3.49 (m, 2 H), 2.11-1.78 (m, 2 H).

Example 35N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxido-8-phenoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

4-(4-Chloro-6-methylquinolin-2-yl)-8-phenoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol1,1-dioxide (250.0 mg, 0.65 mmol, prepared in analogy to4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol1,1-dioxide in Example 34), iodo-benzene (0.1 mL, 0.089 mmol), copper(I)iodide (74.0 mg, 0.35 mmol), N,N-dimethylglycine hydrochloride (72.0 mg,0.52 mmol) and potassium carbonate (267.0 mg, 1.9 mmol) in dimethylsulfoxide (1.5 mL). The reaction mixture was heated with stirring at120° C. for 6 hours. After being cooled to room temperature, thereaction mixture was extracted with ethyl acetate (150 mL×2), washedwith water (50 mL×2) and a saturated aqueous ammonium chloride solution(50 mL×2), dried over anhydrous sodium sulfate and then concentrated invacuo to afford 298.0 mg of the crude product as a yellow oil which wasused for next step without further purification. MS obsd. (ESI⁺)[(M+H)⁺] 465.

N-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-2-(1,1-dioxido-8-phenoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A mixture solution of4-(4-chloro-6-methylquinolin-2-yl)-8-phenoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (167.0 mg, 0.36 mmol),(3-(aminomethyl)-N,N-dibenzyloxetan-3-amine (609.0 mg, 2.16 mmol),1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II) (15.0 mg,0.02 mmol), 1,1′-bis(diphenylphosphino)-ferrocene (11.2 mg, 0.02 mmol)and sodium tert-butoxide (75.0 mg, 0.72 mmol) in 1,4-dioxane (2.0 mL)was heated with stirring at 120° C. for 2 hours under microwaveirridiation. After being cooled to room temperature, the reactionmixture was extracted with ethyl acetate (100 mL). The organic layer waswashed with brine (50 mL×2), dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by ISCO combi-flashchromatography (gradient elution, 20-60% ethyl acetate in petroleumether) to afford 134.6 mg of the desired product as a light yellow solid(yield was 52.6%). MS obsd. (ESI⁺) [(M+H)⁺] 711.

N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxido-8-phenoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A mixture ofN-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(1,1-dioxido-8-phenoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(90 mg, 0.13 mmol), palladium hydroxide on carbon (40 mg) andtrifluoroacetic acid (0.1 mL) in methanol (30.0 mL) was stirred at roomtemperature under hydrogen (2 bar) for 14 hours. Then the reactionmixture was filtered and concentrated in vacuo. The residue was purifiedby preparative HPLC to afford 10.5 mg of the desired product as a whitesolid (yield was 15.2%). MS obsd. (ESI⁺) [(M+H)⁺] 531, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.86 (d, J=8.34 Hz, 1 H), 7.69 (s, 1 H), 7.52 (d, J=2.53Hz, 1 H), 7.45 (d, J=8.59 Hz, 1 H), 7.42-7.35 (m, 2 H), 7.31 (dd,J=8.46, 1.64 Hz, 1 H), 7.25-7.13 (m, 2 H), 7.06-6.97 (m, 2 H), 6.21 (s,1 H), 5.14 (brs, 2 H), 4.70-4.46 (m, 6 H), 3.68 (s, 2 H), 3.60 (brs, 2H), 2.44 (s, 3 H).

Example 36-1N^(˜)3^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninamide

MethylN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninate

To a solution ofN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alanine(85 mg, 0.2 mmol, prepared in analogy to the one in Example 14-2) inmethanol (10 mL) at 0° C. was added thionyl chloride (1.5 mL) carefully.The mixture was stirred at room temperature for 20 minutes, and thenrefluxed at 80° C. for 2 hours. After being cooled to room temperature,the mixture was concentrated in vacuo. The residue was dissolved indichloromethane, washed with a saturated aqueous solution of sodiumbicarbonate, water and brine, then dried over sodium sulfate, andconcentrated in vacuo to afford the crude product which was directlyused for the next step without further purification.

N^(˜)3^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninamide

A mixture of methylN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninateand a solution of ammonia in methanol (7 N, 10 mL) was heated withstirring at 85° C. in a sealed tube overnight. The resulting mixture wasconcentrated in vacuo. The residue was purified by preparative HPLC toafford 59.2 mg of the desired product as a solid. MS obsd. (ESI⁺)[(M+H)⁺] 425, ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (d, J=6.82 Hz, 1 H),7.88 (dd, J=7.83, 1.26 Hz, 1 H), 7.66-7.60 (m, 2 H), 7.50-7.42 (m, 2 H),7.31 (d, J=8.59 Hz, 1 H), 7.22 (dd, J=8.46, 1.64 Hz, 1 H), 6.97 (brs, 1H), 6.73 (t, J=5.68 Hz, 1 H), 6.06 (s, 1 H), 5.06 (brs, 2 H), 4.40 (brs,2 H), 3.68-3.56 (m, 2 H), 3.51 (q, J=6.65 Hz, 2 H), 2.42 (t, J=7.07 Hz,2 H), 2.34 (s, 3 H).

Example 36-23-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}butanamide

The title compound was prepared in analogy to Example 36-1 in Scheme 13by using3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}butanoicacid (prepared in analogy toN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninein Example 14-2). MS obsd. (ESI⁺) [(M+H)⁺] 439, ¹H NMR (400 MHz, CD₃OD)δ ppm 8.07 (dd, J=7.83, 1.26 Hz, 1 H), 7.98 (d, J=7.6 Hz, 1 H), 7.95(brs, 1 H), 7.74-7.66 (m, 2 H), 7.62-7.51 (m, 2 H), 6.14 (s, 1 H), 5.29(s, 2 H), 4.43-4.64 (m, 2 H), 4.38 (q, J=8 Hz, 1 H), 3.72 (brs, 2 H),2.68 (dd, J=14.65, 5.56 Hz, 1 H), 2.54 (dd, J=14.65, 7.07 Hz, 1 H), 2.46(s, 3 H), 1.41 (d, J=6.32 Hz, 3 H).

Example 36-33-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropanamide

The title compound was prepared in analogy to Example 36-1 by using3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropanoicacid (prepared in analogy toN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninein Example 14-2). MS obsd. (ESI⁺) [(M+H)⁺] 439, ¹H NMR (400 MHz,DMSO-d6) δ ppm 8.17 (s, 1 H), 7.99-7.82 (m, 2 H), 7.72-7.57 (m, 2 H),7.54-7.43 (m, 1 H), 7.38 (brs, 1 H), 7.32 (d, J=8.34 Hz, 1 H), 7.23 (dd,J=8.59, 1.52 Hz, 1 H), 6.94 (s, 1 H), 6.03 (s, 1 H), 5.08 (brs, 2 H),4.52 (brs, 3 H), 4.30 (brs, 1 H), 3.70-3.55 (m, 2 H), 3.50 (dt, J=13.26,6.51 Hz, 2 H), 3.25-3.15 (m, 2 H), 2.67 (q, J=6.91 Hz, 1 H), 2.41-2.26(m, 3 H), 1.13 (d, J=7.07 Hz, 3 H).

Example 36-4N^(˜)2^(˜)-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-L-alaninamide

The title compound was prepared in analogy to Example 36-1 by usingN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-L-alanine(prepared in analogy toN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninein Example 14-2). MS obsd. (ESI⁺) [(M+H)⁺] 425, ¹H NMR (400 MHz,DMSO-d6) δ ppm 7.91-7.81 (m, 3 H), 7.68 (s, 1 H), 7.54 (brs, 1 H), 7.48(d, J=7.33 Hz, 1 H), 7.33 (d, J=8.34 Hz, 1 H), 7.26 (d, J=8.08 Hz, 1 H),7.18 (brs, 1 H), 6.61 (d, J=6.32 Hz, 1 H), 5.89 (s, 1 H), 4.99 (brs, 2H), 4.08 (brs, 2 H), 3.59 (brs, 3 H), 2.35 (brs, 3 H), 1.49 (d, J=6.82Hz, 3 H).

Example 36-5N^(˜)2^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycinamide

The title compound was prepared in analogy to Example 36-1 by usingN^(˜)2^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycine(prepared in analogy toN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninein Example 14-2). MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz,DMSO-d6) δ ppm 7.87 (d, J=7.83 Hz, 1 H), 7.82 (d, J=7.33 Hz, 1 H),7.74-7.64 (m, 2 H), 7.52-7.41 (m, 2 H), 7.36-7.30 (m, 1 H), 7.30-7.19(m, 2 H), 7.10 (t, J=5.56 Hz, 1 H), 5.87 (s, 1 H), 5.00 (brs, 2 H), 3.86(d, J=5.81 Hz, 2 H), 3.59 (brs, 2 H), 3.32 (s, 2 H), 2.41-2.32 (s, 3 H).

Example 36-6N^(˜)2^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-methylglycinamide

The title compound was prepared in analogy to Example 36-1 by usingN^(˜)2^(˜)-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycine(prepared in analogy toN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninein Example 14-2) and a solution of methylamine in ethanol. MS obsd.(ESI⁺) [(M+H)⁺] 425, ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.90-7.82 (m, 2 H),7.77 (d, J=7.58 Hz, 1 H), 7.70 (s, 1 H), 7.61 (td, J=7.45, 1.52 Hz, 1H), 7.51-7.46 (m, 1 H), 7.34 (d, J=8.34 Hz, 1 H), 7.26 (dd, J=8.46, 1.64Hz, 1 H), 7.15 (t, J=5.94 Hz, 1 H), 5.86 (s, 1 H), 5.00 (brs, 2 H), 3.90(d, J=5.81 Hz, 2 H), 3.59 (brs, 2 H), 3.32 (s, 2 H), 2.62 (d, J=4.55 Hz,3 H), 2.37 (s, 3 H).

Example 37-1(2S)-2-Amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol

tert-Butyl(2S)-4-({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (332 mg, 0.890 mmol), tert-butyl(2S)-4-aminomethyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (205 mg,0.890 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (73 mg,0.089 mmol), 1,1′-bis(diphenylphosphino)ferrocene (49 mg, 0.089 mmol),sodium tert-butoxide (171.1 mg, 1.780 mmol) and 1,4-dioxane (4 mL) washeated at 120° C. for 1.5 hours under microwave irradiation. Thereaction mixture was concentrated in vacuo. The residue was purified byflash column chromatography to afford 251 mg of the desired product.

(2S)-2-Amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol

A mixture of tert-butyl4-({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(251 mg) and a solution of hydrochloride in ethyl acetate (13 mL, 4 N)was stirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo. The residue was dissolved in water, and basifiedwith a saturated aqueous solution of sodium bicarbonate to about pH 9,and extracted with ethyl acetate (20 mL×3). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate,concentrated in vacuo. The residue was purified by preparative HPLC togive 74.6 mg of the desired product as a white solid. MS obsd. (ESI⁺)[(M+H)⁺] 427, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.04 (dd, J=1.2, 8.0 Hz, 1H), 7.98 (d, J=7.2 Hz, 1 H), 7.86 (s, 1 H), 7.72-7.66 (m, 2 H),7.55-7.46 (m, 2 H), 6.20 (s, 1 H), 5.31 (s, 2 H), 4.57 (s, 2 H),3.93-3.62 (m, 7 H), 2.47 (s, 3 H).

Example 37-2(2R)-2-Amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol

The title compound was prepared in analogy to Example 37-1 in Scheme 14by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide, tert-butyl(2R)-4-aminomethyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate. MS obsd.(ESI⁺) [(M+H)⁺] 427, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.02 (d, J=6.8 Hz, 1H), 7.96 (d, J=8.4 Hz, 1 H), 7.80 (s, 1 H), 7.68 (dd, J=6.0, 7.6 Hz, 1H), 7.58 (d, J=8.4 Hz, 1 H), 7.50 (m, 1 H), 7.41 (d, J=8.4 Hz, 1 H),6.19 (s, 1 H), 5.27 (s, 2 H), 4.57 (s, 2 H), 3.92-3.60 (m, 7 H), 2.45(s, 3 H).

Example 38-1N-[(2-Amino-4,5-dihydro-1,3-oxazol-5-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A mixture of1-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-2-ol(80 mg, 0.18 mmol, prepared in analogy to Example 9-7) and potassiumacetate (89 mg, 0.91 mmol) in a mixture solution of methanol and water(7 ml, V/V=6/1) was added cyanogen bromide (89 mg, 0.84 mmol) at 0° C.After being stirred at room temperature for 3 hours, the mixture wasstirred further with concentrated hydrochloric acid (3 mL) for 1 hour,and then concentrated in vacuo. The residue was dissolved in a saturatedaqueous solution of sodium bicarbonate (10 mL) and extracted withdichloromethane (15 mL×3). The combined organic layers were dried oversodium sulfate and concentrated in vacuo. The residue was purified byflash column (10% methanol in dichloromethane) to afford 32 mg of thedesired product as a white solid. MS obsd. (ESI⁺) [(M+H)⁺] 452, ¹H NMR(400 MHz, DMSO-d6) δ ppm 7.92-7.87 (m, J=4.6 Hz, 2 H), 7.72 (s, 1 H),7.65-7.62 (t, J=3.7 Hz, 1 H), 7.49-7.45 (t, J=3.9 Hz, 1 H), 7.32 (d,J=2.1 Hz, 1 H), 7.23 (d, J=2.1 Hz, 1 H), 6.85 (t, J=2.6 Hz, 1 H), 6.46(brs, 2 H), 6.10 (s, 1 H), 5.10 (s, 2 H), 4.82-4.77 (m, J=4.8 Hz, 1 H),4.49 (brs, 2 H), 3.75 (m, 1 H), 3.63 (s, 2 H), 3.52 (m, 3 H), 2.35 (s, 3H).

Example 38-2N-[(2-Amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

To a mixture of1-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropan-2-ol(200 mg, 0.45 mmol, prepared in analogy to Example 11-4) and potassiumacetate (240 mg, 2.4 mmol) in methanol (8 mL) and water (2 mL) which wascooled to 0° C., a cooled solution of cyanogen bromide (52.3 mg, 0.5mmol) in methanol (2 mL) was added. After being stirred at roomtemperature for 4 hours, the reaction mixture was concentrated in vacuo.The residue was diluted with ethyl acetate (50 mL), washed with water(50 mL), dried over sodium sulfate, and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel to give 80mg of the product as a white powder. MS obsd. (ESI⁺) [(M+H)⁺] 466, ¹HNMR (400 MHz, CD₃OD) δ ppm 7.95 (d, J=7.6 Hz, 1 H), 7.83 (d, J=7.2 Hz, 1H), 7.60 (m, 2 H), 7.46-7.39 (m, 2 H), 7.29 (dd, J=1.6, 8.8 Hz, 1 H),6.19 (s, 1 H), 5.18-5.09 (m, 2 H), 4.51 (brs, 2 H), 3.82 (d, J=11.2 Hz,1 H), 3.65 (s, 2 H), 2.57 (m, 3 H), 2.41 (s, 3 H), 1.62 (s, 3 H).

Example 38-3N-{[(4R)-2-Amino-4,5-dihydro-1,3-oxazol-4-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 38-1 in Scheme 15by using(2R)-2-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol(prepared in analogy to Example 37-2). MS obsd. (ESI⁺) [(M+H)⁺] 452, ¹HNMR (400 MHz, CD₃OD) δ ppm 7.98 (d, J=7.2 Hz, 1 H), 7.87 (d, J=7.2 Hz, 1H), 7.64-7.58 (m, 2 H), 7.47-7.41 (m, 2 H), 7.28 (dd, J=2.0, 8.8 Hz, 1H), 6.09 (s, 1 H), 5.16 (s, 2 H), 4.58 (brs, 2 H), 4.40 (t, J=8.0 Hz, 1H), 4.29 (td, J=5.6, 12.8 Hz, 1 H), 4.20 (dd, J=6.0, 8.0 Hz, 1 H), 3.58(t, J=4.8 Hz, 2 H), 3.45-3.35 (m, 2 H), 2.42 (s, 3 H).

Example 38-4N-{[(4S)-2-Amino-4,5-dihydro-1,3-oxazol-4-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 38-1 in Scheme 15by using(2S)-2-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol(prepared in analogy to Example 37-1). MS obsd. (ESI⁺) [(M+H)⁺] 452, ¹HNMR (400 MHz, CD₃OD) δ ppm 7.98 (d, J=7.2 Hz, 1 H), 7.87 (d, J=7.2 Hz, 1H), 7.64-7.58 (m, 2 H), 7.47-7.41 (m, 2 H), 7.28 (dd, J=2.0, 8.8 Hz, 1H), 6.09 (s, 1 H), 5.16 (s, 2 H), 4.58 (brs, 2 H), 4.40 (t, J=8.0 Hz, 1H), 4.29 (td, J=5.6, 12.8 Hz, 1 H), 4.20 (dd, J=6.0, 8.0 Hz, 1 H), 3.58(t, J=4.8 Hz, 2 H), 3.45-3.35 (m, 2 H), 2.42 (s, 3 H).

Example 38-5cis-5-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-2-amine

To a mixture ofcis-4-amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol(90 mg 0.20 mmol, prepared in analogy to Example 19-3 in Scheme 7 byusing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and tert-butyl [cis-4-hydroxypyrrolidin-3-yl]carbamate) andsodium acetate (82 mg, 1.0 mmol) in methanol (10 mL) at 0° C. was addedcyanogen bromide (105 mg, 1 mmol). The mixture was stirred overnightgradually from 0° C. to room temperature, and then concentrated invacuo. The residue was purified by preparative HPLC to afford the pureproduct as a solid. MS obsd. (ESI⁺) [(M+H)⁺] 464, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.09 (d, J=7.33 Hz, 1 H), 7.98 (d, J=7.58 Hz, 1 H), 7.89(brs, 1 H), 7.79-7.70 (m, 2 H), 7.66-7.56 (m, 2 H), 6.50 (s, 1 H),5.89-5.84 (m, 1 H), 5.41 (brs, 2 H), 4.97-5.02 (m, 1 H), 4.63 (brs, 2H), 4.31 (brs, 1 H), 4.12 (brs, 1 H), 3.77 (brs, 2 H), 3.62-3.42 (b, 2H), 2.54-2.48 (m, 3 H).

Example 392-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

2-{[(1E)-1-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethylidene]amino}-5-methylbenzonitrile

To a stirred solution of1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (6.0 g,25.0 mmol) in dry dichloromethane (100 mL) was added phosphorusoxychloride (2.5 mL, 27.3 mmol) at 10° C. After being stirred for 20minutes at room temperature, a solution of 2-amino-5-methylbenzonitrile(3.3 g, 25.0 mmol) in dry dichloromethane (40 mL) was added and theresulting suspension was heated under reflux for 24 hours. After beingcooled to room temperature, the reaction mixture was diluted with water(50 mL), basified with a saturated aqueous solution of sodiumbicarbonate to about pH 8. The separated aqueous layer was extractedwith dichloromethane (100 mL). The combined organic layers were washedwith brine, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (elutingwith 16% ethyl acetate in petroleum ether) to give 1.5 g of the productas a white solid.

2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A mixture of2-{[(1E)-1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethylidene]amino}-5-methylbenzonitrile(1.5 g, 4.24 mmol), zinc chloride (578 mg, 4.24 mmol) andN,N-dimethylacetamide (4 mL) was heated with stirring at 160° C. for 3hours under argon. After the reaction mixture was cooled to about 40°C., an aqueous solution of sodium hydroxide (2 N, 20 mL) was introduced.After being stirred for 10 minutes at room temperature, the reactionmixture was poured into water. The formed solid was collected byfiltration, and dried in vacuo to give 1.5 g of the product as a brownpowder. MS obsd. (ESI⁺) [(M+H)⁺] 354, ¹H NMR (400 MHz, DMSO-d6) δ ppm7.90-7.84 (m, 2 H), 7.66-7.62 (m, 2 H), 7.48 (t, J=7.2 Hz, 1 H), 7.32(d, J=8.4 Hz, 1 H), 7.23 (dd, J=1.6, 8.8 Hz, 1 H), 6.29 (s, 2 H), 6.23(s, 1 H), 4.97 (s, 2 H), 4.36 (brs, 2 H), 3.60 (t, J=4.8 Hz, 2 H), 2.34(s, 3 H).

Example 40-1N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycinamide

2-Chloro-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]acetamide

To a solution of2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(500 mg, 1.4 mmol) in chloroform (10 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL, 2.8 mmol) followed bychloroacetyl chloride (0.17 mL, 2.1 mmol) at room temperature. Theresulting solution was heated with stirring at 70° C. for 2 hours undernitrogen. After being cooled to room temperature, the reaction wasdiluted with ethyl acetate (50 mL), washed with water (50 mL×3), driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel (eluting with 25% ethyl acetatein petroleum ether) to give 120 mg of the product as an off-white solid.

2-Azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]acetamide

To a solution of2-chloro-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]acetamide(120 mg, 0.28 mmol) in acetonitrile (3 mL) was added sodium azide (72mg, 1.1 mmol). The resulting mixture was stirred at room temperature for6 hours. The reaction was diluted with ethyl acetate (20 mL), washedwith water (10 mL), dried over sodium sulfate, and concentrated invacuo. The residue was purified by column chromatography on silica gel(20% ethyl acetate in petroleum ether) to give 110 mg of the product asa white powder.

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycinamide

To a solution of2-azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]acetamide(110 mg, 0.25 mmol) in methanol was added 10% palladium on carbon (507mg). After being stirred at room temperature overnight under a hydrogenatmosphere, the resulting mixture was filtered. The filtrate wasconcentrated in vacuo. The residue was purified by preparative HPLC toafford 30 mg of the product as a white powder. MS obsd. (ESI⁺) [(M+H)⁺]411, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1 H), 8.12 (s, 1 H), 8.07(d, J=7.6 Hz, 1 H), 8.00 (d, J=7.6 Hz, 1 H), 7.87 (d, J=8.8 Hz, 1 H),7.67-7.12 (m, 2 H), 7.57 (t, J=8.0 Hz, 1 H), 5.31 (s, 2 H), 4.66 (brs, 2H), 4.25 (s, 2 H), 3.78 (s, 2 H), 2.52 (s, 3 H).

Example 40-2N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylalaninamide

2-Bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropanamide

To a solution of2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(200 mg, 0.566 mmol) in chloroform (10 mL) was added triethylamine(0.124 mL), followed by 2-bromo-2-methylpropionyl chloride (286 mg, 1.30mmol). The resulting mixture was heated at 110° C. for 2 hours undermicrowave irradiation. After being cooled to room temperature, themixture was concentrated in vacuo. The residue was diluted with ethylacetate (35 mL), washed with brine and dried over sodium sulfate, andconcentrated in vacuo. The residue was purified by flash chromatographyto afford 180 mg of the title compound as a light solid (yield was 63%).

2-Azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropanamide

To a solution of2-bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropanamide(160 mg, 0.319 mmol) in actonitrile (15 mL) was added sodium azide (62mg, 0.958 mmol). After being refluxed overnight, the resulting mixturewas concentrated in vacuo. The residue was diluted with ethyl acetate(40 mL), washed with brine, dried over sodium sulfate, and concentratedin vacuo to afford 160 mg of the crude product.

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylalaninamide

To a solution2-azido-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropanamide(160 mg, 0.345 mmol) in ethyl acetate (25 mL) was added 10% palladium oncarbon (100 mg), the flask was degassed and refilled with hydrogen(repeated for three times). After being stirred at room temperatureovernight under a hydrogen atmosphere, the resulting mixture wasfiltered. The filtrate was concentrated in vacuo. The residue waspurified by flash chromatography to afford 110 mg of the title compound(yield was 73%). MS obsd. (ESI⁺) [(M+H)⁺] 439, ¹H NMR (400 MHz, CDCl₃) δppm 11.05 (s, 1 H), 8.30 (s, 1 H), 8.02 (dd, J=0.8, 7.6 Hz, 1 H), 7.89(d, J=7.2 Hz, 1 H), 7.59 (d, J=8.8 Hz, 1 H), 7.53 (t, J=7.6 Hz, 1 H),7.37 (m, 3 H), 5.17 (s, 2 H), 4.6 (brs., 2 H), 3.56 (s, 2 H), 2.48 (s, 3H), 1.56 (s, 6 H).

Example 40-3N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]alaninamide

The title compound was prepared in analogy to Example 40-2 in Scheme 18by using2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine,2-bromopropionyl chloride and sodium azide. MS obsd. (ESI⁺) [(M+H)⁺]425, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.07-7.85 (m, 3 H), 7.64-7.51 (m, 2H), 7.46-7.35 (m, 2 H), 5.22-5.08 (m, 2 H), 4.51-4.42 (m, 1 H),3.65-3.53 (m, 2 H), 3.37 (s, 3 H), 2.51-2.40 (m, 3 H), 1.73 (d, J=7.07Hz, 1 H), 1.30 (d, J=2.78 Hz, 2 H).

Example 40-42-Amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]butanamide

The title compound was prepared in analogy to Example 40-2 in Scheme 18by using2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine,2-bromobutyryl chloride and sodium azide. MS obsd. (ESI⁺) [(M+H)⁺] 439,¹H NMR (400 MHz, CD₃OD) δ ppm 8.07 (m, 3 H), 7.53 (m, 2 H), 7.45 (m, 2H), 5.33 (m, 2 H), 4.32 (m, 1 H), 3.59 (m, 2 H), 3.37 (s, 3 H), 2.44 (m,2 H), 1.70 (d, J=8.02 Hz, 1 H), 1.38 (d, J=2.56 Hz, 2 H), 1.22 (m, 3 H).

Example 41N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methoxy-2-methylpropanamide

To a solution of2-bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropanamide(80 mg, 0.159 mmol, prepared in Example 40-2) in methanol (5 mL) wasadded ethylamine (1 mL), the resulting mixture was heated under refluxovernight. After being cooled to room temperature, the resulting mixturewas concentrated in vacuo. The residue was purified by preparative TLC(eluting with 33% ethyl acetate in hexanes) to afford 15 mg of the titlecompound as a light powder (yield was 21%). MS obsd. (ESI⁺) [(M+H)⁺]454, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.94-7.89 (m, 3 H), 7.58 (m, 2 H),7.43-7.39 (m, 3 H), 5.17 (s, 2 H), 4.50 (brs, 2 H), 3.59 (m, 2 H), 3.50(s, 3 H), 2.46 (s, 3 H), 1.56 (s, 6 H).

Example 42-1N^(˜)1^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4,4-trifluorobutane-1,3-diamine

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanamide

To a solution of2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(200 mg, 0.565 mmol, prepared in analogy to the one in Example 2-1) inN,N-dimethylformamide (6 mL) was added a solution of3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoylchloride (670 mg, 2.3 mmol) in dichloromethane (4 mL) followed byN,N-diisopropylethylamine (0.3 mL). The resulting mixture was stirred atroom temperature for 1 hour and heated at 85° C. for additional 2 hours.After being cooled to room temperature, the resulting mixture wasevaporated in vacuo. The residue was diluted with water and extractedwith ethyl acetate (20 mL×2). The combined organic layers were washedwith brine, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by flash chromatography to afford 230 mg of theproduct as a solid (yield was 66%).

3-Amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4,4-trifluorobutanamide

To a solution ofN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanamide(25 mg, 0.04 mmol) in ethanol (3 mL) was added a solution of methylamine(30% in ethanol, 0.3 mL). The resulting mixture was heated at 90° C. for2 hours. After being cooled to room temperature, the mixture wasconcentrated in vacuo. The residue was purified by flash chromatography(eluting with 50% ethyl acetate in hexanes) to afford 15 mg of the titlecompound as light solid (yield was 80%).

N^(˜)1^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4,4-trifluorobutane-1,3-diamine

To a solution of3-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4,4-trifluorobutanamide(120 mg, 0.245 mmol) was added a solution of borane-methyl sulfidecomplex in methyl sulfide (5 M, 1.0 mL). The resulting solution washeated at 85° C. for 2 hours. After being cooled to room temperature,the mixture was acidified by careful addition of an aqueous solution ofhydrochloric acid (1 M) to about pH 4, and then stirred at roomtemperature overnight. The resulting mixture was concentrated in vacuo.The residue was neutralized with a 10% aqueous solution of sodiumhydroxide to pH >9, and then extracted with dichloromethane (20 mL×3).The combined organic layers were washed with brine, dried over sodiumsulfate, and concentrated in vacuo. The residue was purified by flashchromatography to afford 60 mg of the title product as a solid (yieldwas 65%). MS obsd. (ESI⁺) [(M+H)⁺] 479, ¹H NMR (400 MHz, CDCl₃) δ ppm8.04 (d, J=7.6 Hz, 1 H), 7.65 (d, J=7.6 Hz, 1 H), 7.50-7.49 (m, 2 H),7.38 (t, J=7.2 Hz, 1 H), 7.30 (m, 1 H), 6.06 (s, 1 H), 5.93 (s, 1 H),5.12 (s, 1 H), 3.63 (m, 3 H), 4.62 (brs, 2 H), 3.45 (m, 1 H), 3.33 (m, 1H), 2.42 (s, 3 H), 2.22 (m, 1 H), 2.03 (s, 1 H), 1.82 (m, 1 H).

Example 42-2N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninamide

The title compound was prepared in analogy to3-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4,4-trifluorobutanamidein Example 42-1 in Scheme 19 by using2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amineand 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride. MSobsd. (ESI⁺) [(M+H)⁺] 425, ¹H NMR (400 MHz, CDCl₃) δ ppm 8.00 (d, J=7.83Hz, 1 H), 8.29 (s, 1 H), 7.85 (d, J=7.33 Hz, 1 H), 7.61-7.47 (m, 4 H),7.34 (d, J=12.13 Hz, 2 H), 5.12 (s, 2 H), 3.55 (brs, 2 H), 3.23 (d,J=5.56 Hz, 2 H), 2.62 (brs, 2 H), 2.44 (brs, 3 H), 1.66-2.10 (m, 2 H).

Example 432-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-{[3-(ethylamino)oxetan-3-yl]methyl}-6-methylquinolin-4-amine

To a stirred solution ofN-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(200 mg, 0.46 mmol, prepared in analogy to Example 2-2), acetaldehyde(25.6 μL, 0.46 mmol) and acetic acid (270 μL) in methanol (8 mL) wasadded dropwize a solution of sodium cyanoborohydride (34 mg, 0.54 mmol)in tetrahydrofuran (0.5 mL). After being stirred for 12 hours at roomtemperature, the reaction mixture was diluted with ethyl acetate, washedwith water and a saturated aqueous solution of sodium bicarbonate, driedover sodium sulfate, and concentrated in vacuo. The residue was purifiedby preparative HPLC to afford 42 mg of the desired product as a whitesolid (yield was 20%). MS obsd. (ESI⁺) [(M+H)⁺] 467, ¹H NMR (400 MHz,DMSO-d6) δ ppm 7.95 (d, J=1.9 Hz, 1 H), 7.89-7.87 (t, J=2.2 Hz, 1 H),7.64-7.58 (m, J=6.0 Hz, 2 H), 7.49-7.45 (m, J=4.0 Hz, 1 H), 7.35 (d,J=2.1 Hz, 1 H), 7.27-7.24 (m, J=2.5 Hz, 1 H), 6.17 (s, 1 H), 5.11 (s, 2H), 4.52 (d, 2 H), 4.37 (d, 4 H), 3.62-3.45 (t, J=2.4 Hz, 2 H), 3.58 (d,2 H), 2.53 (m, 2 H), 2.37 (s, 3 H), 1.07-1.03 (t, J=3.6 Hz, 3 H).

Example 44-12-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[1-(oxetan-3-yl)pyrrolidin-3-yl]quinolin-4-amine

To a solution of[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine(21 mg, 0.05 mmol, prepared in analogy to Example 21-4) and oxetan-3-one(7.2 mg, 0.10 mmol) in tetrahydrofuran (2 mL) was added acetic acid (8.6μL, 0.15 mmol). After the mixture being stirred at 55° C. for 1 hour,sodium triacetoxyborohydride (21 mg, 0.10 mmol) was added to themixture. After being stirred for 2 hours at 65° C., the reaction mixturewas concentrated in vacuo. The residue was portioned between ethylacetate and a saturated aqueous solution of sodium carbonate. Theseparated organic layer was washed with water, dried over sodiumsulfate, and concentrated in vacuo. The residue was purified bypreparative HPLC to afford 10 mg of the product as a white solid. MSobsd. (ESI⁺) [(M+H)⁺] 479, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.30 (d, J=1.9Hz, 1 H), 7.84 (d, J=1.8 Hz, 1 H), 7.78 (s, 1 H), 7.68-7.64 (t, J=3.7Hz, 1 H), 7.53-7.49 (t, J=3.7 Hz, 2 H), 7.39 (d, J=1.7 Hz, 1 H), 5.98(s, 1 H), 5.20 (s, 2 H), 4.83-4.78 (m, J=4.7 Hz, 2 H), 4.69-4.60 (m,J=8.4 Hz, 2 H), 4.55 (brs, 2 H), 4.37 (s, 1 H), 3.80-3.74 (m, J=4.1 Hz,1 H), 3.65-3.61 (m, J=4.2 Hz, 2 H), 2.96-2.89 (m, J=6.6 Hz, 2 H),2.75-2.72 (m, J=3.3 Hz, 1 H), 2.63-2.47 (m, J=15.9 Hz, 2 H), 2.45 (s, 3H), 1.95 (m, 1 H).

Example 44-2N′-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-ethyl-N-(oxetan-3-yl)ethane-1,2-diamine

The title compound was prepared in analogy to Example 44-1 in Scheme 20by usingN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-ethylethane-1,2-diamine(prepared in analogy to Example 3-37) and oxetan-3-one. MS obsd. (ESI⁺)[(M+H)⁺] 481, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.02 (d, J=7.6 Hz, 1 H),7.87 (d, J=7.2 Hz, 1 H), 7.66 (t, 2 H), 7.50 (t, 2 H), 7.36 (d, J=7.6Hz, 1 H), 6.04 (s, 1 H), 5.20 (s, 2 H), 4.68-4.50 (m, 6 H), 4.07-4.00(m, 1 H), 3.65 (s, 2 H), 3.45 (t, J=12.4 Hz, 2 H), 2.84 (t, J=12.8 Hz, 2H), 2.73-2.67 (m, 2 H), 2.45 (s, 3 H), 1.07 (t, 3 H).

Example 45-1N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(oxetan-3-yl)propane-1,3-diamine

To a stirred ofN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,3-diamine(84 mg, 0.2 mmol, prepared in analogy to Example 9-3), oxetan-3-one (15mg, 0.21 mmol) and ethyldiisopropylamine (43 μL, 0.25 mmol) indichloromethane (10 mL) was added molecular sieves (4 Å, 84 mg) followedby sodium triacetoxyborohydride (63.6 mg, 0.3 mmol). After being stirredat room temperature overnight, another batch of sodiumtriacetoxyborohydride (63.6 mg, 0.3 mmol) was added and the mixture washeated under reflux for 2 hours. The reaction mixture was cooled, washedwith brine, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by preparative HPLC to afford 26 mg ofN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(oxetan-3-yl)propane-1,3-diamineas a white solid. MS obsd. (ESI⁺) [(M+H)⁺] 467, ¹H NMR (400 MHz, CD₃OD)δ ppm 8.05 (d, J=7.6 Hz, 1 H), 7.87 (d, J=7.6 Hz, 1 H), 7.34 (s, 1 H),7.68 (t, J=14.8 Hz, 1 H), 7.58-7.51 (m, 2 H), 7.45 (d, 1 H), 5.99 (s, 1H), 5.24 (s, 2 H), 4.85 (t, J=3.3 Hz, 2 H), 4.85 (t, J=13.6 Hz, 2 H),4.55 (m, 4 H), 4.06-4.00 (m, 1 H), 3.67 (s, 2 H), 3.50 (t, J=13.2 Hz, 2H), 2.74 (t, J=13.6 Hz, 2 H), 2.45 (s, 3 H), 1.98-1.91 (m, 2 H).

Example 45-21-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-(oxetan-3-yl)pyrrolidin-3-amine

The title compound was prepared in analogy to Example 45-1 in Scheme 20by using1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amineand oxetan-3-one (prepared in analogy to Example 25) and oxetan-3-one.MS obsd. (ESI⁺) [(M+H)⁺] 479, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.99-7.97(m, J=2.2 Hz, 1 H), 7.83-7.80 (t, J=2.9 Hz, 2 H), 7.64-7.60 (m, J=4.1Hz, 1 H), 7.47-7.43 (m, J=4.5 Hz, 2 H), 7.29-7.26 (m, J=2.5 Hz, 1 H),6.12 (s, 1 H), 5.15 (s, 2 H), 4.85 (m, 2 H), 4.56 (m, 4 H), 4.14 (m, 1H), 3.73 (m, 2 H), 3.60 (m, 3 H), 3.42 (m, 2 H), 2.40 (s, 3 H), 2.21 (m,1 H), 1.87 (m, 1 H).

Example 45-3N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(oxetan-3-yl)ethane-1,2-diamine

The title compound was prepared in analogy to Example 45-1 in Scheme 20by usingN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(oxetan-3-yl)ethane-1,2-diamine(prepared in analogy to Example 9-16) and oxetan-3-one. MS obsd. (ESI⁺)[(M+H)⁺] 453, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.09 (t, J=2.0 Hz, 1 H),7.87 (d, J=1.7 Hz, 2 H), 7.74-7.70 (m, J=4.0 Hz, 1 H), 7.64 (d, J=2.1Hz, 1 H), 7.61-7.54 (m, J=6.8 Hz, 2 H), 6.03 (s, 1 H), 5.29 (s, 2 H),4.85 (t, J=3.3 Hz, 2 H), 4.51 (t, J=3.1 Hz, 4 H), 4.06 (brs, 1 H), 3.73(s, 2 H), 3.57 (t, J=3.0 Hz, 2 H), 2.93 (brs, 2 H), 2.48 (s, 3 H).

Example 46N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(pyridin-2-yl)ethane-1,2-diamine

A mixture ofN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine(150 mg, 0.38 mol, prepared in analogy to Example 9-16),2-bromo-pyridine (60 mg, 0.38 mol),tri(dibenzylideneacetone)dipalladium(0) (17.4 mg, 0.019 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthe (22 mg, 0.038 mmol),cesium carbonate (247.6 mg, 0.76 mmol) and N-methylpyrrolidinone (3 mL)was heated with stirring at 150° C. for 6 hours under nitrogen. Themixture was diluted with ethyl acetate, washed with water, dried oversodium sulfate, filtered, concentrated in vacuo. The residue waspurified by preparative HPLC to give 10 mg of produce as an off-whitesolid. MS obsd. (ESI⁺) [(M+H)⁺] 474, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.1(d, J=6.4 Hz, 1 H), 7.96 (dd, J=1.2, 8.0 Hz, 1 H), 7.81 (d, J=6.8 Hz, 1H), 7.54-7.39 (m, 5 H), 7.27 (dd, J=2.0, 8.8 Hz, 1 H), 6.63-6.56 (m, 2H), 6.07 (s, 1 H), 5.10 (s, 2 H), 4.52 (brs, 2 H), 3.69 (t, J=6.4 Hz, 2H), 3.55 (m, 4 H), 2.40 (s, 3 H).

Example 47-1(4R)-1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-hydroxypyrrolidin-2-one

A mixture of4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (400 mg, 0.96 mol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1), (4R)-4-hydroxypyrrolidin-2-one (116.3 mg,1.15 mmol), copper(I) iodide (90 mg, 0.47 mmol), potassium carbonate(265 mg, 1.92 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.1 mL,0.63 mmol) and diethylene glycol dimethyl ether (10 mL) was heated withstirring in a 10 mL of microwave process vial for 2 hours at 140° C. Themixture was diluted with dichloromethane, washed with water. The aqueouswas back extracted with dichloromethane. The combined organic layer wasdried over sodium sulfate, filtered, concentrated in vacuo. The residuewas purified by column chromatography on silica gel to give 160 mg ofproduce as a gray solid. MS obsd. (ESI⁺) [(M+H)⁺] 438, ¹H NMR (400 MHz,DMSO-d6) δ ppm 7.96 (d, J=7.2 Hz, 1 H), 7.88 (dd, J=1.2, 8.0 Hz, 1 H),7.64 (td, J=1.2, 7.6 Hz, 1 H), 7.56 (d, J=8.8 Hz, 1 H), 7.48 (dd, J=6.8,7.6 Hz, 1 H), 7.40 (m, 2 H), 7.24 (s, 1 H), 5.51 (d, J=3.6 Hz, 1 H),5.13 (s, 2 H), 5.55 (d, J=2.4 Hz, 1 H), 4.41 (brs, 2 H), 4.08 (dd,J=4.8, 10.0 Hz, 1 H), 3.66 (s, 2 H), 3.52 (d, J=9.6 Hz, 1 H), 2.87 (dd,J=6.4, 16.8 Hz, 1 H), 2.36 (dd, J=2.0, 16.8 Hz, 1 H), 2.36 (s, 3 H).

Example 47-2N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-5-oxopyrrolidine-3-carboxamide

A mixture of4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (500 mg, 1.19 mol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1), 5-oxopyrrolidine-3-carboxamide (307 mg,2.39 mmol), copper(I) iodide (23 mg, 0.12 mmol), potassium carbonate(497 mg, 3.60 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.038mL, 0.24 mmol) and diethylene glycol dimethyl ether (10 mL) was heatedwith stirring in a 10 mL microwave process vial for 3 hours at 140° C.under microwave irridiation. The mixture was diluted withdichloromethane, washed with water. The aqueous layer was back extractedwith dichloromethane. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel to give 40 mg ofN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-5-oxopyrrolidine-3-carboxamideas light brown solid. MS obsd. (ESI⁺) [(M+H)⁺] 451, ¹H NMR (400 MHz,DMSO-d6) δ ppm 9.98 (s, 1 H), 7.88 (m, 3 H), 7.81 (s, 1 H), 7.70 (s, 1H), 7.64 (td, J=1.2, 7.6 Hz, 1 H), 7.47 (d, J=8.8 Hz, 1 H), 7.46 (dd,J=0.8, 7.6 Hz, 1 H), 7.38 (dd, J=1.6, 8.4 Hz, 1 H), 5.08 (s, 2 H), 4.42(brs, 2 H), 3.73-3.57 (m, 4 H), 3.43 (dd, J=6.0, 9.6 Hz, 1 H), 3.32 (s,1 H), 2.48 (m, 1 H), 2.42 (s, 3 H).

Example 47-32-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(1H-pyrazol-3-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 47-1 in Scheme 5by using4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and 1H-pyrazol-3-amine. MS obsd. (ESI⁺)[(M+H)⁺] 420, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.22 (s, 1 H), 8.15-8.14 (d,J=2.8 Hz, 1 H), 8.04-8.02 (d, J=8 Hz, 1 H), 7.90-7.88 (d, J=7.2 Hz, 1H), 7.85-7.83 (d, J=8.8 Hz, 1 H), 7.71-7.70 (m, 1 H), 7.64-7.61 (d,J=8.4 Hz, 1 H), 7.60-7.51 (t, J=8 Hz, 1 H), 7.30 (s, 1 H), 6.27 (s, 1H), 5.34 (s, 2 H), 4.59 (s, 2 H), 3.74 (s, 2 H), 2.45 (s, 3 H).

Example 47-4N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyridine-3-carboxamide

The title compound was prepared in analogy to Example 47-1 in Scheme 5by using4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and pyridine-3-carboxamide. MS obsd. (ESI⁺)[(M+H)⁺] 459, ¹H NMR (400 MHz, CD₃OD) δ ppm 9.17 (s, 1 H), 8.80 (s, 1H), 8.52 (s, 1 H), 8.44-8.42 (d, J=8 Hz, 1 H), 8.08-8.06 (d, J=8 Hz, 1H), 7.99-7.96 (d, J=9.6 Hz, 2 H), 7.90-7.88 (d, J=8.4 Hz, 1 H),7.70-7.48 (m, 4 H), 5.29 (s, 2 H), 4.72 (s, 2 H), 3.64 (s, 2 H), 2.49(s, 3 H).

Example 47-5N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-2-carboxamide

The title compound was prepared in analogy to Example 47-1 in Scheme 5by using4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and piperidine-2-carboxamide. MS obsd.(ESI⁺) [(M+H)⁺] 465, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.33 (s, 1 H),8.07-8.05 (d, J=6.8 Hz, 1 H), 8.02 (s, 1 H), 7.95-7.93 (d, J=7.6 Hz, 1H), 7.80-7.78 (d, J=8.4 Hz, 1 H), 7.66-7.62 (q, J=8.8 Hz, 2 H),7.56-7.52 (dd, J=7.2, 15.6 Hz, 1 H), 5.28 (s, 2 H), 4.61 (s, 2 H),4.34-4.31 (dd, J=2.4, 12.8 Hz, 1 H), 3.74 (s, 2 H), 3.56-3.53 (d, J=12.8Hz, 1 H), 3.18-3.11 (m, 1 H), 2.51 (s, 3 H), 2.46-2.43 (d, J=14 Hz, 1H), 2.07-1.99 (m, 2 H), 1.88-1.76 (m, 1 H).

Example 47-6N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-(pyridin-2-yl)acetamide

The title compound was prepared in analogy to Example 47-1 in Scheme 5by using4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and 2-(pyridin-2-yl)acetamide. MS obsd.(ESI⁺) [(M+H)⁺] 473, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.53 (s, 1 H), 8.15(s, 2 H), 8.06-8.04 (d, J=7.6 Hz, 1 H), 7.85-7.54 (m, 8 H), 5.26 (s, 2H), 4.61 (s, 2 H), 3.57 (s, 2 H), 2.56 (s, 3 H).

Example 47-7N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]methanesulfonamidetrifluoroacetate

The title compound was prepared in analogy to Example 47-1 in Scheme 5by using4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and methanesulfonamide. MS obsd. (ESI⁺)[(M+H)⁺] 432, ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.98-7.90 (m, 2 H),7.88-7.82 (d, J=7.2 Hz, 1 H), 7.72-7.65 (t, J=2 Hz, 1 H), 7.65-7.58 (d,J=7.6 Hz, 1 H), 7.58-7.51 (t, J=2.4 Hz, 1 H), 7.48-7.42 (d, J=7.6 Hz, 1H), 7.01 (s, 1 H), 5.10 (s, 2 H), 4.60-4.40 (m, 2 H), 3.82-3.75 (t,J=2.8 Hz, 2 H), 3.10 (s, 3 H), 2.38 (s, 3 H).

Example 47-8N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrazine-2-carboxamide

The title compound was prepared in analogy to Example 47-1 in Scheme 5by using4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and pyrazine-2-carboxamide. MS obsd. (ESI⁺)[(M+H)⁺] 460, ¹H NMR (400 MHz, CD₃OD) δ ppm 9.53 (s, 1 H), 8.97 (s, 1H), 8.86 (s, 1 H), 8.72 (s, 1 H), 8.10-8.08 (dd, J=5.2, 11.2 Hz, 2 H),7.94-7.90 (dd, J=8.8, 14.8 Hz, 2 H), 7.76-7.72 (d, J=7.6 Hz, 2 H),7.60-7.56 (d, J=8 Hz, 1 H), 5.37 (s, 2 H), 4.70 (s, 2 H), 3.81 (s, 2 H),2.56 (s, 3 H).

Example 47-9N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-hydroxyacetamide

The title compound was prepared in analogy to Example 47-1 in Scheme 5by using4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and 2-hydroxyacetamide. MS obsd. (ESI⁺)[(M+H)⁺] 412, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.54 (s, 1 H), 8.05 (dd,J=1.2, 7.6 Hz, 1 H), 7.97 (d, J=7.2 Hz, 1 H), 7.81 (s, 2 H), 7.70-7.66(m, 2 H), 7.54 (t, J=7.6 Hz, 1 H), 5.27 (s, 2 H), 4.62 (s, 2 H), 4.36(s, 2 H), 3.76 (s, 2 H), 2.51 (s, 3 H).

Example 48N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyridine-2-carboxamide

A mixture of pyridine-2-carboxylic acid amide (99 mg, 0.8 mmol),4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (300 mg, 0.8 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1), cyclohexane-1,3-diamine (90 mg, 0.08mmol), copper(I) iodide (1.5 mg, 0.008 mmol) and potassium phosphate(340 mg, 1.6 mmol) in 1,4-dioxane (3 mL) was heated in a 5 mL ofmicrowave process vial for 3 hours at 150° C. The reaction mixture wasconcentrated in vacuo. The residue was purified by preparative HPLC andSPE to give 26 mg of the desired product (yield was 7.1%). MS obsd.(ESI⁺) [(M+H)⁺] 451, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.90-8.82 (d, J=8 Hz,1 H), 8.77 (s, 1 H), 8.47-8.40 (d, J=7.6 Hz, 1 H), 8.20-8.13 (t, J=6.4Hz, 1 H), 8.13-8.08 (d, J=7.6 Hz, 2 H), 7.92-7.85 (m, 2 H), 7.80-7.70(q, J=8.4 Hz, 3 H), 7.62-7.56 (t, J=7.2 Hz, 1 H), 5.37 (s, 2 H),4.80-4.50 (m, 2 H), 3.82-3.78 (t, J=2.8 Hz, 2 H), 2.60 (s, 3 H).

Example 49N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]azetidine-2-carboxamide

tert-Butyl2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbamoyl}azetidine-1-carboxylate

The title compound was prepared in analogy to Example 48-1 in Scheme 5by using4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and tert-butyl2-carbamoylazetidine-1-carboxylate.

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]azetidine-2-carboxamide

To a solution of tert-butyl2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbamoyl}azetidine-1-carboxylate(80 mg, 0.15 mmol) in ethyl acetate (10 mL) was added a solution ofhydrochloride in ethyl acetate (4 N, 30 mL) dropwise in an ice-waterbath. After being stirred at room temperature for 4 hours, the resultingmixture was concentrated in vacuo and purified by preparative HPLC togive the trifluoroacetic acid salt of the desired product. Thetrifluoroacetic acid salt was flashed through SPE column with methanol.The eluent was concentrated in vacuo and dried by lyopylization to give30.79 mg of the desired product (yield was 47%). MS obsd. (ESI⁺)[(M+H)⁺] 437, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.35 (s, 1 H), 8.04 (dd,J=1.2, 7.6 Hz, 1 H), 7.98 (d, J=7.6 Hz, 1 H), 7.93 (s, 1 H), 7.75 (d,J=8.8 Hz, 1 H), 7.67 (t, J=7.6 Hz, 1 H), 7.59 (d, J=9.6 Hz, 1 H), 7.53(t, J=8.8 Hz, 1 H), 5.47-5.43 (m, 1 H), 5.28 (s, 2 H), 4.61 (brs, 2 H),4.25-4.18 (m, 1 H), 4.14-4.10 (m, 1 H), 3.73 (s, 2 H), 3.04-2.98 (m, 1H), 2.76-2.72 (m, 1 H), 2.49 (s, 3 H).

Example 50-11-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-phenylurea

To a solution of2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(180 mg, 0.5 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and triethylamine (103 mg) intetrahydrofuran (15 mL) was added a solution of isocyanato-benzene (59.6mg, 0.5 mmol) in tetrahydrofuran (5 mL) at 0° C. The reaction wasstirred at room temperature overnight and then heated at 50° C. foradditional 5 hours. The reaction mixture was concentrated in vacuo andthe residue was purified by preparative HPLC and SPE to give 17.6 mg ofthe desired product (yield was 7.5%). MS obsd. (ESI⁺) [(M+H)⁺] 473, ¹HNMR (400 MHz, CD₃OD) δ ppm 8.55 (s, 1 H), 8.12-8.03 (m, 2 H), 7.92 (s, 1H), 7.86-7.81 (d, J=8.4 Hz, 1 H), 7.76-7.68 (m, 2 H), 7.66-7.57 (m, 3H), 7.45-7.38 (t, J=7.6 Hz, 2 H), 7.20-7.12 (t, J=2.0 Hz, 1 H), 5.32 (s,2 H), 4.61-4.40 (m, 2 H), 3.82-3.75 (t, J=2.8 Hz, 2 H), 2.56 (s, 3 H).

Example 50-21-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-ethylurea

The title compound was prepared in analogy to Example 50-1 by using2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and ethylisocyanate. MS obsd. (ESI⁺)[(M+H)⁺] 425, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.44 (s, 1 H), 8.09-8.03 (d,J=8 Hz, 1 H), 7.99-7.93 (d, J=7.6 Hz, 1 H), 7.86 (s, 1 H), 7.80-7.74 (d,J=8.8 Hz, 1 H), 7.72-7.62 (m, 2 H), 7.60-7.51 (t, J=8.4 Hz, 1 H), 5.24(s, 2 H), 4.62-4.50 (m, 2 H), 3.78-3.70 (m, 2 H), 3.40-3.32 (q, J=7.2Hz, 2 H), 2.49 (s, 3 H), 1.28-1.20 (t, J=7.2 Hz, 3 H).

Example 51N-[6-Cyclopropyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine

4-(4-Chloro-6-cyclopropylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

To a solution of4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (1.0 g, 2.3 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) in toluene (150 mL) was addedcyclopropylboronic acid (200 mg, 2.3 mmol), palladium acetate (52 mg,0.23 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (143 mg, 0.23mmol) and potassium carbonate (320 mg, 2.3 mmol) under argon protection.After being heated at 90° C. for 16 hours, the reaction mixture wasconcentrated in vacuo. The residue was dissolved in dichloromethane (100mL), and the solution was washed with water (50 mL×3), dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (eluting with 16% ethyl acetate in petroleumether) to afford 300 mg of the desired product (yield was 33%).

N-[6-Cyclopropyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine

A mixture of4-(4-chloro-6-cyclopropylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (300 mg, 0.75 mmol) and propane-1,3-diamine (700 mg, 7.5mmol) was heated with stirring in a 10 mL of microwave process vial for1.5 hours at 150° C. under microwave irradiation. The reaction mixturewas purified by preparative HPLC to give the trifluoroacetic acid saltof the desired product. The trifluoroacetic acid salt was flashedthrough SPE column with methanol. The eluent was concentrated in vacuoand dried by lyopylization to give 119.4 mg of the desired product(yield was 36%). MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR (400 MHz, CD₃OD) δppm 8.05 (d, J=7.6 Hz, 1 H), 7.84 (d, J=7.2 Hz, 1 H), 7.81 (d, J=1.2 Hz,1 H), 7.67-7.69 (m, 2 H), 7.55 (t, J=7.6 Hz, 1 H), 7.46 (d, J=8.8 Hz, 1H), 5.92 (s, 1 H), 5.29 (s, 2 H), 4.48 (brs, 2 H), 3.70 (s, 2 H), 3.59(t, J=6.8 Hz, 2 H), 3.08 (t, J=8.0 Hz, 2 H), 2.12-2.07 (m, 2 H),2.05-1.98 (m, 1 H), 1.03 (dd, J=2.0 Hz, 8.4 Hz, 2 H), 0.78-0.76 (m, 2H).

Example 524-[(3-Aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carbonitrile

4-(4-Chloro-6-ethynylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

To a degassed solution of4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (880 mg, 2 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) in N,N-dimethylformamide (50 mL), zinccyanide (280 mg, 2.4 mmol) and tetrakis(triphenylphosphine)palladium(0)(232 mg, 0.2 mmol) was added under argon. After being refluxed for 2hours, the reaction mixture was concentrated in vacuo and the residuewas portioned in ethyl acetate (100 mL) and water (100 mL). After beingstirred vigorously for 1 hour, the separated aqueous layer was extractedwith ethyl acetate (100 mL×2). The combined organic layers were driedover sodium sulfate and concentrated in vacuo to afford 0.6 g of thecrude product.

4-[(3-Aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carbonitrile

A mixture of4-(4-chloro-6-ethynylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (300 mg, 0.7 mmol), propane-1,3-diamine (64 mg, 0.8 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (65 mg,0.08 mmol), 1,1′-bis(diphenylphosphino)ferrocene (45 mg, 0.08 mmol) andsodium tert-butoxide (307 mg, 3.2 mmol) in 1,4-dioxane (3 mL) was heatedwith stirring in a sealed 5 mL of microwave process vial for 1.5 hoursat 120° C. under microwave irradiation. The resulting mixture wasconcentrated in vacuo. The residue was purified by preparative HPLC andSPE. After SPE separation, the eluent was concentrated in vacuo and theresidue was dried by lyophylization to afford 65.2 mg of the desiredproduct (yield was 20%). MS obsd. (ESI⁺) [(M+H)⁺] 422, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.60 (s, 1 H), 8.10-8.08 (d, J=8 Hz, 1 H), 7.99-7.86 (m, 3H), 7.74-7.70 (t, J=7.2 Hz, 1 H), 7.61-7.57 (t, J=7.6 Hz, 1 H), 6.05 (s,2 H), 5.35 (s, 2 H), 4.56 (s, 2 H), 3.75 (s, 2 H), 3.62-3.59 (t, J=6.8Hz, 2 H), 3.14-3.10 (t, J=8 Hz, 2 H), 2.15-2.11 (t, J=7.6 Hz, 2 H).

Example 53 N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethenylquinolin-4-yl]propane-1,3-diamine

4-(4-Chloro-6-ethenylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

To a degassed solution of4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (880 mg, 2 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) in N,N-dimethylformamide (50 mL),tributyl(vinyl)tin (760 mg, 2.4 mmol) andtetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) was addedunder argon. After being refluxed for 2 hours, the reaction mixture wasconcentrated in vacuo and the residue was portioned in ethyl acetate(100 mL) and a saturated aqueous solution of potassium fluoride (100mL). After the mixture being stirred vigorously for 1 hour, theseparated aqueous layer was extracted with ethyl acetate (100 mL×2). Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo to afford 0.4 g of the crude product.

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethenylquinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 52 in Scheme 22 byusing4-(4-chloro-6-ethenylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and propane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 423, ¹HNMR (400 MHz, CD₃OD) δ ppm 8.12 (s, 1 H), 8.05-8.02 (q, J=8 Hz, 1 H),7.89-7.81 (m, 2 H), 7.77-7.70 (m, 2 H), 7.56-7.54 (t, J=4.4 Hz, 1 H),6.80-6.74 (m, 1 H), 5.95-5.90 (m, 2 H), 5.36-5.30 (m, 3 H), 4.51 (s, 2H), 3.71 (s, 2 H), 3.61-3.60 (t, J=3.2 Hz, 2 H), 3.11-3.10 (t, J=5.2 Hz,2 H), 2.13-2.11 (t, J=5.6 Hz, 2 H).

Example 54N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethynylquinolin-4-yl]propane-1,3-diamine

4-(4-chloro-6-ethynylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

To a degassed solution of4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (880 mg, 2 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) in N,N-dimethylformamide (50 mL),tributyl(ethynyl)tin (760 mg, 2.4 mmol) andtetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) was addedunder argon. After being refluxed for 2 hours, the reaction mixture wasconcentrated in vacuo and the residue was portioned in a mixture ofethyl acetate (100 mL) and a saturated aqueous solution of potassiumfluoride (100 mL). After the mixture being stirred vigorously for 1hour, the separated aqueous layer was extracted with ethyl acetate (100mL×2). The combined organic layers were dried over sodium sulfate andconcentrated in vacuo to afford 0.45 g of the crude product.

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethynylquinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 52 in Scheme 22 byusing4-(4-chloro-6-ethynylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and propane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 421, ¹HNMR (400 MHz, CD₃OD) δ ppm 8.25 (s, 1 H), 8.01-7.99 (d, J=7.6 Hz, 1 H),7.94-7.92 (d, J=7.2 Hz, 1 H), 7.87-7.85 (d, J=8.8 Hz, 1 H), 7.82-7.79(m, 1 H), 7.65-7.61 (m, 1 H), 7.50-7.47 (m, 1 H), 7.32 (s, 1 H), 5.30(s, 2 H), 3.65-3.60 (m, 6 H), 2.70 (s, 3 H), 2.14-2.11 (t, J=5.2 Hz, 2H).

Example 55-1N-[(3-Aminooxetan-3-yl)methyl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

N-(3-Aminooxetan-3-ylmethyl)-2-chloro-6-methylquinazolin-4-amine

A solution of 2,4-dichloro-6-methylquinazoline (645 mg, 3 mmol) and3-(aminomethyl)oxetan-3-amine (340 mg, 3.3 mmol) in methanol (15 mL) wasstirred at room temperature overnight. After the resulting mixture wasconcentrated in vacuo, the residue was purified by column chromatography(eluting with 10% methanol in dichloromethane) to afford the desiredproduct.

N-[(3-Aminooxetan-3-yl)methyl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

A mixture ofN-(3-aminooxetan-3-ylmethyl)-2-chloro-6-methylquinazolin-4-amine (140mg, 0.5 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (270mg, 1.5 mmol) in n-butanol (10 mL) was heated at 160° C. for 30 minutes.After the resulting mixture was concentrated in vacuo, the residue waspurified by preparative HPLC to afford the pure product as a solid. MSobsd. (ESI⁺) [(M+H)⁺] 424, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.01 (s, 1 H),7.83-7.79 (m, 2 H), 7.66-7.52 (m, 4 H), 5.45-5.41 (d, 1 H), 5.10 (brs, 1H), 4.80-4.72 (m, 6 H), 4.39 (s, 2 H), 3.51 (s, 2 H), 2.45 (s, 3 H).

Example 55-2N-{[3-(Benzylamino)oxetan-3-yl]methyl}-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

The title compound was prepared in analogy to Example 55-1 in Scheme 23by using 2,4-dichloro-6-methylquinazoline,3-(aminomethyl)-N-benzyloxetan-3-amine and2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI⁺) [(M+H)⁺]514, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.06 (s, 1 H), 7.81-7.77 (m, 2 H),7.66-7.56 (m, 4 H), 7.47-7.45 (m, 2 H), 7.31-7.29 (m, 3 H), 5.45-5.35(d, 1 H), 5.10 (brs, 1 H), 4.82-4.80 (m, 6 H), 4.71-4.69 (m, 2 H), 4.16(s, 2 H), 3.51 (m, 2 H), 2.46 (s, 3 H).

Example 55-32-Fluoro-N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 55-1 in Scheme 23by using 2,4-dichloro-6-methylquinazoline, 2-fluoropropane-1,3-diamineand 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI⁺)[(M+H)⁺] 414, ¹H NMR (400 MHz, CD₃OD) δ ppm (d, J=7.6 Hz, 1 H), 7.79 (s,1 H), 7.70-7.20 (m, 6 H), 5.56 (m, 1 H), 4.85-4.55 (m, 3 H), 4.48-4.32(brs, 1 H), 3.91-3.71 (brs, 2 H), 3.40-3.11 (m, 2 H), 2.93-2.72 (m, 2H), 2.24 (s, 3 H), 1.68 (s, 2 H).

Example 55-4N-[2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2,2-difluoropropane-1,3-diamine

The title compound was prepared in analogy to Example 55-1 in Scheme 23by using 2,4-dichloro-6-methylquinazoline,2,2-difluoropropane-1,3-diamine and2,3,4,5-tetrahydro-1,4-benzothiazepine. MS obsd. (ESI⁺) [(M+H)⁺] 416, ¹HNMR (400 MHz, CD₃OD) δ ppm 7.96 (s, 1 H), 7.80-7.68 (m, 1 H), 7.60-7.58(m, 2 H), 7.51-7.49 (m, 1 H), 7.30-7.27 (t, 1 H), 7.24-7.20 (t, 1 H),5.15 (s, 2 H), 4.37-4.31 (m, 4 H), 3.51-3.49 (m, 4 H), 3.14 (s, 2 H),2.45 (s, 3 H).

Example 56-1N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-chloro-6-methylquinazolin-4-amine

To a mixture of oxetane-3,3-diyldimethanamine (1.16 g, 10.0 mmol) andtriethylamine (1.4 mL, 10 mol) in dichloromethane (15 mL) was addeddropwise of a solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.36mmol) in dichloromethane (5 mL). After being stirred at room temperatureovernight, the resulting mixture was diluted with water (50 mL), andextracted with dichloromethane. The organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified by flash column chromatography (eluting with 10%methanol in dichloromethane) to afford 300 mg of the desired product asa white solid.

N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

The title compound was prepared in analogy to Example 55-1 in Scheme 23by usingN-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-chloro-6-methylquinazolin-4-amineand 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide. MS obsd. (ESI⁺)[(M+H)⁺] 454, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.99 (dd, J=7.83, 1.26 Hz, 1H), 7.88 (d, J=7.33 Hz, 1 H), 7.67 (s, 1 H), 7.62 (td, J=7.58, 1.26 Hz,1 H), 7.50-7.37 (m, 2 H), 7.37-7.30 (m, 1 H), 5.21 (brs, 2 H), 4.66 (d,J=6.06 Hz, 2 H), 4.57 (d, J=6.06 Hz, 1 H), 4.51 (d, J=6.32 Hz, 2 H),4.06 (s, 2 H), 3.53 (t, J=5.05 Hz, 2 H), 3.05 (s, 2 H), 2.40 (s, 3 H).

Example 56-22,2-Difluoro-N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 56-1 in Scheme 23by using 2,4-dichloro-6-methylquinazoline,2,2-difluoropropane-1,3-diamine and2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI⁺) [(M+H)⁺]432, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (s, 1 H), 7.82-7.80 (d, 1 H),7.74-7.69 (m, 2 H), 7.63-7.53 (m, 3 H), 5.40 (d, 1 H), 5.10 (m, 1 H),4.75 (m, 1 H), 4.60-4.33 (m, 3 H), 3.63 (m, 4 H), 2.45 (s, 3 H).

Example 56-3N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

The title compound was prepared in analogy to Example 56-1 in Scheme 23by using 2,4,6-trichloroquinazoline, oxetane-3,3-diyldimethanamine and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI⁺)[(M+H)⁺] 474, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.99 (d, J=6.82 Hz, 1 H),7.94 (d, J=2.53 Hz, 1 H), 7.88 (d, J=7.07 Hz, 1 H), 7.66-7.59 (m, 1 H),7.52-7.42 (m, 2 H), 7.42-7.36 (m, 1 H), 5.21 (brs, 2 H), 4.69-4.56 (m, 5H), 4.51 (d, J=6.32 Hz, 2 H), 4.05 (brs, 2 H), 3.52 (t, J=5.05 Hz, 2 H),3.04 (s, 2 H).

Example 56-4N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2,2-difluoropropane-1,3-diamine

The title compound was prepared in analogy to Example 56-1 in Scheme 23by using 2,4-dichloro-6-methylquinazoline,2,2-difluoropropane-1,3-diamine and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI⁺)[(M+H)⁺] 448, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.06-8.04 (dd, J=1.2, 7.6Hz, 1 H), 7.99 (s, 1 H), 7.84-7.82 (d, J=7.6 Hz, 1 H), 7.72-7.67 (m, 2H), 7.63-7.58 (m, 1 H), 7.56-7.54 (dd, J=1.2, 8 Hz, 1 H), 5.35 (s, 2 H),4.54 (s, 2 H), 4.44-4.37 (t, J=14 Hz, 2 H), 3.72-3.64 (m, 4 H), 2.46 (s,3 H).

Example 56-5N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-fluoropropane-1,3-diamine

The title compound was prepared in analogy to Example 56-1 in Scheme 23by using 2,4-dichloro-6-methylquinazoline, 2-fluoropropane-1,3-diamineand 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI⁺)[(M+H)⁺] 430, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.06-8.04 (d, J=7.6 Hz, 1H), 7.93 (s, 1 H), 7.81-7.79 (d, J=7.6 Hz, 1 H), 7.69-7.65 (t, J=8 Hz, 2H), 7.60-7.53 (m, 2 H), 5.32 (s, 2 H), 5.17-5.03 (d, J=28 Hz, 1 H), 4.52(s, 2 H), 4.20-3.92 (m, 2 H), 3.67 (s, 2 H), 3.47-3.36 (m, 2 H), 2.44(s, 3 H).

Example 56-6N-[6-Methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 56-1 in Scheme 23by using 2,4-dichloro-6-methylquinazoline, propane-1,3-diamine and2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI⁺) [(M+H)⁺]396, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.92 (s, 1 H), 7.81-7.79 (d, J=7.6Hz, 1 H), 7.74-7.72 (d, J=7.6 Hz, 1 H), 7.64-7.50 (m, 4 H), 5.43-5.39(d, J=15.6 Hz, 1 H), 5.12-5.05 (m, 1 H), 4.81-4.72 (m, 1 H), 4.53-4.46(m, 2 H), 3.84-3.82 (m, 2 H), 3.52-3.48 (m, 2 H), 3.31-3.29 (m, 2 H),2.43 (s, 3 H), 2.17-2.11 (m, 2 H).

Example 57-1N-[(3-Aminooxetan-3-yl)methyl]-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

N-[(3-Aminooxetan-3-yl)methyl]-2-chloroquinazolin-4-amine

To a solution of 2,4-dichloroquinazoline (1.0 g, 5.024 mmol) in methanol(15 mL) was added 3-(aminomethyl)oxetan-3-amine (855 mg, 60%, 5.024mmol) and triethylamine (101 mg, 1.005 mmol). After being stirred atroom temperature overnight, the mixture was concentrated in vacuo. Theresidue was purified by flash column chromatography to afford 1.2 g ofthe desired product as a white solid (yield was 92%).

N-[(3-Aminooxetan-3-yl)methyl]-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

To a solution ofN-[(3-aminooxetan-3-yl)methyl]-2-chloroquinazolin-4-amine (200 mg, 0.756mmol) in N,N-dimethylformamide (4 mL) was added2,3,4,5-tetrahydro-1,4-benzothiazepine (125 mg, 0.756 mmol) andtriethylamine (230 mg, 2.268 mmol). After being heated at 130° C. for 4hours under microwave irradiation, the reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was dried withsodium sulfate, and concentrated in vacuo. The residue was purified bypreparative HPLC to afford 42 mg of the desired product as a white solid(yield was 14%). MS obsd. (ESI⁺) [(M+H)⁺] 394, ¹H NMR (400 MHz, CD₃OD) δppm 7.75-7.73 (t, J=6.4, 1.2 Hz, 1 H), 7.56-7.53 (m, 1 H), 7.52-7.47 (m,2 H), 7.43-7.41 (d, J=8.0 Hz, 1 H), 7.24-7.20 (m, 1 H), 7.15-7.08 (m, 2H), 5.06 (s, 2 H), 4.69-4.67 (d, J=6.8 Hz, 2 H), 4.55-4.53 (d, J=6.4 Hz,2 H), 4.42 (s, 2 H), 4.09 (s, 2 H), 2.97-2.95 (t, J=4.8, 4.4 Hz, 2 H).

Example 57-2N-[(3-Aminooxetan-3-yl)methyl]-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

The title compound was prepared in analogy to Example 57-1 in Scheme 23by using 2,4-dichloroquinazoline, 3-(aminomethyl)oxetan-3-amine and2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI⁺) [(M+H)⁺]410, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.91-7.90 (t, J=7.2, 0.8 Hz, 1 H),7.81-7.74 (m, 2 H), 7.58-7.54 (m, 1 H), 7.51-7.43 (m, 3 H), 7.16-7.12(m, 1 H), 5.32-5.28 (d, J=15.2 Hz, 2 H), 4.68-4.53 (m, 6 H), 4.10 (s, 2H), 3.37-3.34 (m, 2 H).

Example 57-3N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

The title compound was prepared in analogy to Example 57-1 in Scheme 23by using 2,4-dichloroquinazoline, 3-(aminomethyl)oxetan-3-amine and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI⁺)[(M+H)⁺] 426, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98-7.93 (m, 1 H),7.91-7.88 (m, 2 H), 7.64-7.60 (m, 1 H), 7.57-7.51 (m, 1 H), 7.48-7.41(m, 2 H), 7.15-7.11 (m, 1 H), 5.24 (s, 2 H), 4.67-4.54 (m, 6 H), 4.09(s, 2 H), 3.55-3.50 (m, 2 H).

Example 57-4N-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

The title compound was prepared in analogy to Example 57-1 in Scheme 23by using 2,4,6-trichloroquinazoline, 3-(aminomethyl)oxetan-3-amine and2,3,4,5-tetrahydro-1,4-benzothiazepine. MS obsd. (ESI⁺) [(M+H)⁺] 428, ¹HNMR (400 MHz, DMSO-d6) δ ppm 8.18 (s, 1 H), 7.97 (s, 1 H), 7.70 (s, 1H), 7.51-7.44 (m, 2 H), 7.27-7.21 (m, 2 H), 7.16-7.12 (t, J=7.2 Hz, 1H), 4.93 (s, 2 H), 4.50-4.35 (m, 5 H), 3.97-3.80 (m, 2 H), 2.96-2.87 (m,2 H), 2.69-2.67 (m, 1 H), 2.35-2.33 (m, 1 H), 2.10 (s, 2 H).

Example 57-5N-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

The title compound was prepared in analogy to Example 57-1 in Scheme 23by using 2,4,6-trichloroquinazoline, 3-(aminomethyl)oxetan-3-amine and2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI⁺) [(M+H)⁺]444, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.57 (s, 1 H), 8.01-7.73 (m, 2 H),7.52-7.40 (m, 4 H), 5.31-5.28 (d, J=15.2 Hz, 1 H), 4.66-4.53 (m, 6 H),4.08 (s, 2 H), 3.51-3.50 (m, 2 H), 1.36-1.31 (m, 1 H).

Example 57-6N-[(3-Aminooxetan-3-yl)methyl]-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

The title compound was prepared in analogy to Example 57-1 in Scheme 23by using 2,4,6-trichloroquinazoline, 3-(aminomethyl)oxetan-3-amine and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI⁺)[(M+H)⁺] 460, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.00-7.98 (t, J=2.0, 4.8 Hz,2 H), 7.91-7.89 (d, J=7.2 Hz, 1 H), 7.64-7.60 (t, J=7.2 Hz, 1 H),7.51-7.44 (m, 2 H), 7.40-7.38 (d, J=9.2 Hz, 1 H), 5.22 (s, 2 H),4.65-4.62 (t, J=6.4, 5.6 Hz, 4 H), 4.56-4.54 (d, J=6.4 Hz, 2 H), 4.08(s, 2 H), 3.54-3.51 (t, J=5.2, 4.8 Hz, 2 H).

Example 57-72-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]amino}ethanol

The title compound was prepared in analogy to Example 57-1 in Scheme 23by using 2,4-diichloro-6-methylquinazoline, 2-aminoethanol and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI⁺)[(M+H)⁺] 410, ¹HNMR (400 MHz, CD₃OD) δ ppm 7.98 (dd, J=1.2, 7.6 Hz, 1H), 7.83 (d, J=6.8 Hz, 1 H), 7.63-7.59 (m, 2 H), 7.44 (td, J=0.8, 7.6Hz, 1 H), 7.38 (dd, J=1.6, 8.4 Hz, 1 H), 7.31 (d, J=8.4 Hz, 1 H), 5.20(s, 2 H), 4.58 (brs, 2 H), 3.82-3.78 (m, 4 H), 3.53 (t, J=5.2 Hz, 2 H),2.39 (s, 3 H).

Example 582-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

2-Chloro-6-methylquinazolin-4-amine

A mixture of 2,4-dichloro-6-methylquinazoline (500 mg, 2.348 mmol) and asolution of ammonia in tetrahydrofuran (20 mL, 3.0 M) was stirred in anice-bath for 2 hours. The resulting mixture was concentrated in vauco toafford 454 mg of the crude product as a white solid.

2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

To a solution of 2-chloro-6-methylquinazolin-4-amine (454 mg, 2.345mmol) in n-butanol (5 mL) was added2,3,4,5-tetrahydro-1,4-benzothiazepine (388 mg, 2.345 mmol). After beingheated at 150° C. for 1.5 hours under microwave irradiation, thereaction mixture was filtered and the collected solid was washed withether to afford 756 mg of the product as a white solid. MS obsd. (ESI⁺)[(M+H)⁺] 323, ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (s, 1 H), 7.83-7.81(d, J=8.0 Hz, 1 H), 7.62-7.60 (d, J=8.0 Hz, 1 H), 7.53-7.49 (m, 2 H),7.29-7.25 (m, 1 H), 7.22-7.19 (m, 1 H), 4.98 (s, 2 H), 4.25 (s, 2 H),2.98 (s, 2 H), 2.35 (s, 3 H).

Example 592-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

To a solution of oxone (670 mg, 1.117 mmol) in water (2.5 mL), which wascooled below 0° C. in an ice-bath, was added a solution of2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine(300 mg, 0.930 mmol) in methanol (15 mL) and tetrahydrofuran (3 mL)dropwise. The resulting mixture was stirred below 0° C. for 2 hours. Theformed precipitate was collected by filtration, washed with water anddried in vacuo to afford the desired product as a white solid. MS obsd.(ESI⁺) [(M+H)⁺] 355, ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.91-7.86 (m, 2 H),7.77 (s, 1 H), 7.64-7.60 (t, J=16.0 Hz, 1 H), 7.51-7.48 (m, 2 H),7.37-7.35 (d, J=8.0 Hz, 1 H), 5.06 (s, 2 H), 4.37 (s, 2 H), 3.59 (s, 2H), 2.31 (s, 3 H).

Example 60N^(˜)1^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-methylpropane-1,2-diamine

N^(˜)1^(˜)-(2-Chloro-6-methylquinazolin-4-yl)-2-methylpropane-1,2-diamine

A solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.35 mmol) and2-methylpropane-1,2-diamine (365 μL, 3.52 mmol) in methanol (10 mL) wasstirred at room temperature for 1 hour. The reaction mixture was dilutedwith ethyl acetate (30 mL) and stirred for 30 minutes. The formed solidwas collected by filtration and dried in vacuo to afford 500 mg of thedesired product as a white solid (yield was 80.6%).

N^(˜)1^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-methylpropane-1,2-diamine

A mixture ofN^(˜)1^(˜)-(2-chloro-6-methylquinazolin-4-yl)-2-methylpropane-1,2-diamine(300 mg, 1.14 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine (226 mg,1.25 mmol) in n-butanol (3 mL) was heated in the microwave at 160° C.for 2 hours. The resulting mixture was concentrated in vacuo. Theresidue was purified by flash column chromatography (eluting with 0-10%methanol in dichloromethane) to afford 300 mg of the desired product asa white solid (yield was 67%).

N^(˜)1^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-methylpropane-1,2-diamine

To a stirred solution ofN^(˜)1^(˜)-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-methylpropane-1,2-diamine(240 mg, 0.61 mmol) in dichloromethane (15 mL) was added3-chloroperoxybenzoic acid (263 mg, 1.53 mmol) at 0° C. After beingstirred at 0° C. for 20 minutes, the reaction mixture was washed with asaturated aqueous solution of sodium carbonate and brine, dried oversodium sulfate, and concentrated in vacuo. The residue was purified byflash column chromatography (eluting with 10% methanol indichloromethane) to afford 100 mg of the desired product as a whitesolid (yield was 38.6%). MS obsd. (ESI⁺) [(M+H)⁺] 426, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.99 (d, J=1.9 Hz, 1 H), 7.86 (d, J=1.8 Hz, 1 H), 7.73 (s,1 H), 7.60 (t, J=2.7 Hz, 1 H), 7.47-7.40 (m, J=6.9 Hz, 2 H), 7.36-7.33(m, 1 H), 5.20 (s, 2 H), 4.58 (brs, 2 H), 3.72 (s, 2 H), 3.52 (m, 2 H),2.41 (s, 3 H), 1.30 (s, 6 H).

Example 61-1N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

N-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

A mixture of(2-chloro-6-methylquinazolin-4-yl)-[3-(dibenzylamino)oxetan-3-ylmethyl]-amine(2 g, 4.4 mmol, prepared in analogy toN-(3-aminooxetan-3-ylmethyl)-2-chloro-6-methylquinazolin-4-amine inExample 55-1), 2,3,4,5-tetrahydro-1,4-benzothiazepine (720 mg, 4.4mmol), triethylamine (1.2 mL, 8.6 mmol) in N,N-dimethylformamide (20 mL)was heated with stirring in a 30 mL of microwave process vial for 2hours at 150° C. The reaction mixture was diluted with ethyl acetate,washed with water and brine. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel to give 1.7 g of the product as awhite solid.

N-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

To a solution ofN-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine(1.7 g, 2.89 mmol) in dichloromethane (30 mL) was added3-chloroperbenzoic acid (75%, 1.33 g, 5.8 mmol) at 0° C. The resultingmixture was stirred for 1 hour whilst allowing the temperature to riseslowly to room temperature. The reaction mixture was then washed with asaturated aqueous solution of sodium carbonate, a saturated aqueoussolution of sodium sulfite and brine. The organic layer was dried oversodium sulfate, filtered, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel to give 1.4 g of theproduct as a white solid.

N-[(3-Aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

To a solution of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine(1.4 g, 2.26 mmol) in methanol was added palladium hydroxide (20% oncarbon, 200 mg). After being stirred at room temperature overnight undera hydrogen atmosphere, the resulting mixture was filtered. The filtratewas concentrated in vacuo. The residue was purified by columnchromatography on silica gel to afford 300 mg of the product asoff-white foam. MS obsd. (ESI⁺) [(M+H)⁺] 440, ¹H NMR (400 MHz, CD₃OD) δppm 7.97 (d, J=7.6 Hz, 1 H), 7.86 (d, J=7.2 Hz, 1 H), 7.69 (s, 1 H),7.58 (t, J=7.2 Hz, 1 H), 7.44-7.34 (m, 3 H), 5.21 (s, 2 H), 4.66 (d,J=6.4 Hz, 2 H), 4.60 (br.s., 2 H), 4.56 (d, J=6.4 Hz, 2 H), 4.10 (s, 2H), 3.52 (t, J=5.2 Hz, 2 H), 2.39 (s, 3 H).

Example 61-2N-[(1-Aminocyclobutyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

N-[(1-Benzylamino-cyclobutyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

The title compound was prepared in analogy toN-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-aminein Example 61-1 in Scheme 24 by using 2,4-dichloro-6-methylquinazoline,1-(aminomethyl)-N-dibenzylcyclobutanamine and2,3,4,5-tetrahydro-1,4-benzothiazepine.

N-[(1-Aminocyclobutyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

A mixture ofN-[(1-benzylamino-cyclobutyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine(220 mg, 0.417 mmol), 10% of palladium hydroxide on carbon (30 mg), andtrifluoroacetic acid (160 μL) in methanol (20 mL) was stirred at roomtemperature for 24 hours under a hydrogen atmosphere. The resultingmixture was filtered, and the filtrate was adjusted to pH 8-9 by theaddition of a solution of ammonia in methanol (7 M), and concentrated invacuo. The residue was purified by preparative HPLC to give 105 mg ofthe product as a white solid. MS obsd. (ESI⁺) [(M+H)⁺] 438, ¹H NMR (400MHz, CD₃OD) δ ppm 7.98 (d, J=7.6 Hz, 1 H), 7.86 (d, J=7.6 Hz, 1 H), 7.73(s, 1 H), 7.60 (t, J=7.6 Hz, 1 H), 7.47-7.32 (m, 3 H), 5.33 (s, 2 H),4.58 (brs, 2 H), 3.84 (s, 2 H), 3.53 (t, J=4.8 Hz, 2 H), 2.41 (s, 3 H),2.21 (m, 2 H), 2.04-1.97 (m, 2 H), 1.91-1.82 (m, 2 H).

Example 62-1N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

2-Chloro-6-methylquinazolin-4(3H)-one

To a solution of 2,4-dichloro-6-methylquinazoline (2.13 g, 10 mmol) intetrahydrofuran (20 mL) was added sodium hydroxide (2 N, 20 mL). Afterbeing stirred at room temperature for 4 hours, the reaction mixture waschilled and acidified to pH 5 with acetic acid. The formed solid wascollected by filtration, washed with water, and dried in vacuo to afford1.7 g of the desired product as a white solid (yield was 87.6%).

6-Methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one

To a stirred solution of 2-chloro-6-methylquinazolin-4(3H)-one (15 g,77.3 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (16.8 g,103 mmol) in toluene (200 mL) was added triethylamine (16.1 mL, 116mmol). After being refluxed overnight, the reaction mixture was cooledto room temperature. The formed solid was collected by filtration,washed with ethanol (50 mL) and ethyl acetate (100 mL), and then driedin vacuo to afford 21.0 g of the desired product as a white solid (yieldwas 80%).

N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

To a solution of6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one(10 g, 29.5 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (16.9 g, 38.3 mmol) in N,N-dimethylformamide (140mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (6.7 g, 44.2 mmol) atroom temperature. After being stirred for 10 minutes,(3-aminomethyl-oxetan-3-yl)-methylamine (5.1 g, 44.2 mmol) was added.The mixture was stirred for 4 hours at room temperature and diluted withwater (150 mL). The separated aqueous layer was extracted with ethylacetate (100 mL×6). The organic layers were combined and washed withbrine, dried over sodium sulfate, and then concentrated in vacuo. Theresidue was purified by flash column chromatography (eluting with 10%methanol in dichloromethane) to afford 9.0 g of the impure product(purity was 90%). The impure product was purified by preparative HPLC toafford 6.0 g of the desired product as a white solid. MS obsd. (ESI⁺)[(M+H)⁺] 438, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.02 (s, 1 H), 7.82-7.79 (m,2 H), 7.64 (d, J=1.6 Hz, 1 H), 7.60-7.57 (m, 3 H), 5.44 (d, 1 H), 5.13(brs, 1 H), 4.77 (brs, 1 H), 4.66-4.59 (m, 4 H), 4.51 (brs, 1 H), 4.24(s, 2 H), 3.55 (brs, 2 H), 3.44 (s, 2 H), 2.44 (s, 3 H).

Example 62-2 and Example 62-3(−)-N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-[(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinazolin-4-amineand(+)-N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinazolin-4-amine

The chiral separation of Example 62-1 (column: IA; flow rate: 15 mL/min;gradient: 50% hexane in ethanol with 0.4% of triethylamine) affords(−)-N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinazolin-4-amine,MS obsd. (ESI⁺) [(M+H)⁺] 438, and(+)-N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinazolin-4-amine,MS obsd. (ESI⁺) [(M+H)⁺] 438.

Example 62-4 and Example 62-5N^(˜)4^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-fluorobutane-1,4-diamineandN^(˜)1^(˜)-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-fluorobutane-1,4-diamine

The title compound was prepared in analogy to Example 62-1 in Scheme 23by using 2-chloro-6-methylquinazolin-4(3H)-one,2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and2-fluorobutane-1,4-diamine. 8.65 mg of compound A and 3.54 mg ofcompound B were obtained.

A: MS obsd. (ESI⁺) [(M+H)⁺] 444, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.03-7.90(d, J=3 Hz, 1 H), 7.65 (s, 1 H), 7.50-7.40 (t, 1 H), 7.40-7.30 (m, 3 H),7.15 (s, 1 H), 5.95 (s, 1 H), 5.10 (s, 2 H), 4.75-4.50 (d, J=52 Hz, 2H), 3.75 (s, 2 H), 3.40 (s, 2 H), 2.97-2.87 (m, 2 H), 2.34 (s, 3 H),1.90 (s, 2 H).

B: MS obsd. (ESI⁺) [(M+H)⁺] 444, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.03-7.90(d, J=4 Hz, 1 H), 7.70 (s, 1 H), 7.45-7.35 (t, 1 H), 7.33-7.25 (m, 3 H),6.10 (s, 1 H), 5.15 (s, 2 H), 4.90-4.50 (m, 3 H), 4.00-3.65 (m, 2 H),3.40 (s, 2 H), 2.95-2.70 (m, 2 H), 2.30 (s, 3 H), 2.11-1.65 (m, 2 H).

Example 62-6N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

The title compound was prepared in analogy to Example 62-1 in Scheme 23by using 2-chloro-6-methylquinazolin-4(3H)-one,2,3,4,5-tetrahydro-1,4-benzothiazepine andoxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 422. ¹H NMR (400MHz, CD₃OD) δ ppm 7.66 (dd, J=1.6, 7.2 Hz, 1 H), 7.62 (s, 1 H), 7.44(dd, J=1.2, 7.6 Hz, 1 H), 7.34-7.29 (m, 2 H), 7.18 (m, 1 H), 7.08 (m, 1H), 4.99 (s, 2 H), 4.63 (d, J=6.4 Hz, 2 H), 4.45 (d, J=6.4 Hz, 2 H),4.34 (s, 2 H), 4.02 (s, 2 H), 2.98 (s, 2 H), 2.90 (m, 2 H), 2.36 (s, 3H).

Example 62-7trans-4-Fluoro-1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-amine

The title compound was prepared in analogy to Example 62-1 in Scheme 23by using 2-chloro-6-methylquinazolin-4(3H)-one,2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide andtrans-4-fluoropyrrolidin-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 426. ¹H NMR(400 MHz, CD₃OD) 7.82 (s, 1 H), 7.71 (d, J=6.8 Hz, 1 H), 7.42 (m, 4 H),5.26 (d, J=15.2 Hz, 1 H), 5.07 (d, J=51.2 Hz, 1 H), 4.78 (brs, 1 H),4.43 (m, 2 H), 4.29 (m, 1 H), 4.06 (t, J=11.2 Hz, 1 H), 3.86 (d, J=12Hz, 1 H), 3.75 (m, 1 H), 3.40 (m, 2 H), 2.40 (s, 3 H).

Example 63-1N-(2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}ethyl)acetamide

To a solution ofN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine(39 mg, 0.1 mmol, prepared in analogy to Example 9-11) indichloromethane (5 mL) was added acetic anhydride (12 mg, 0.12 mmol) at0° C. The reaction mixture was stirred at room temperature for 2 hoursand then concentrated in vacuo. The residue was diluted with a saturatedaqueous solution of sodium bicarbonate (5 mL), and extracted withdichloromethane (10 mL×2). The combined organic layers were washed withbrine (10 mL), dried over sodium sulfate, filtered and concentrated invacuo. The residue was purified by flash column chromatography (elutingwith 10% methanol in dichloromethane) to afford 21 mg of the desiredproduct as a white solid (yield was 48%). MS obsd. (ESI⁺) [(M+H)⁺] 439,¹H NMR (400 MHz, CD₃OD) δ ppm 8.16 (s, 1 H), 7.95 (d, J=1.8 Hz, 2 H),7.86 (d, J=1.9 Hz, 1 H), 7.62 (t, J=3.6 Hz, 2 H), 7.46 (t, J=3.8 Hz, 1H), 7.31 (d, J=2.1 Hz, 1 H), 7.22 (d, J=2.1 Hz, 1 H), 6.84 (s, 1 H),6.20 (s, 1 H), 5.10 (s, 2 H), 4.43 (brs, 2 H), 3.62 (s, 2 H), 3.32 (m, 4H), 2.34 (s, 3 H), 1.89 (s, 3 H).

Example 63-2 N-{[3-({[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}methyl)oxetan-3-yl]methyl}acetamide

The title compound was prepared in analogy to Example 63-1 in Scheme 25by usingN-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(prepared in analogy to Example 3-50) and acetic anhydride. MS obsd.(ESI⁺) [(M+H)⁺] 495, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.00 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.2 Hz, 1 H), 7.66 (t, 2 H), 7.46 (t, 2 H), 7.32-7.30 (m,1 H), 6.22 (s, 1 H), 5.17 (s, 2 H), 4.56-4.51 (m, 6 H), 3.67 (d, 4 H),3.60 (t, J=9.6 Hz, 2 H), 2.43 (s, 3 H), 2.06 (s, 3 H).

Example 63-3N-(3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propyl)acetamide

The title compound was prepared in analogy to Example 63-1 in Scheme 25by usingN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,3-diamine(prepared in analogy to Example 9-3) and acetic anhydride. MS obsd.(ESI⁺) [(M+H)⁺] 453, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.00-7.97 (m, 1 H),7.81 (d, J=7.2 Hz, 1 H), 7.76-7.64 (m, 2 H), 7.46-7.42 (m, 2 H),7.30-7.28 (m, 1 H), 5.99 (s, 1 H), 5.14 (s, 2 H), 4.54 (brs, 2 H), 3.58(t, 2 H), 3.36 (m, 4 H), 2.42 (s, 3 H), 2.00 (s, 3 H), 1.94-1.87 (m, 2H).

Example 63-4N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]acetamide

A mixture of2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine(50 mg, 0.14 mmol, prepared in analogy to Example 59) and aceticanhydride (2 mL) was heated with stirring at 110° C. for 2 hours undernitrogen. The reaction mixture was diluted with ethyl acetate, washedwith a saturated aqueous solution of sodium carbonate and brine, driedover sodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica gel to give 30 mg of theproduct as a white powder. MS obsd. (ESI⁺) [(M+H)⁺] 397, ¹H NMR (400MHz, CD₃OD) δ ppm 7.87 (d, J=7.6 Hz, 1 H), 7.80 (s, 1 H), 7.56 (m, 3 H),7.28 (m, 1 H), 7.21 (m, 1 H), 5.11 (s, 2 H), 4.48 (s, 2 H), 2.99 (s, 2H), 2.47 (s, 6 H).

Example 641-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-methylpyrrolidin-3-amine

N-{1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-methylpyrrolidin-3-yl}acetamide

The title compound was prepared in analogy to Example 3-1 in Scheme 26by using4-(4-chloro-6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to the one in Example 2-1) andN-(3-methylpyrrolidin-3-yl)acetamide.

1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-methylpyrrolidin-3-amine

A mixture ofN-{1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-methylpyrrolidin-3-yl}acetamide(102 mg, 0.21 mmol) and hydrochloric acid (2 N, 120 mL) was heated withstirring at 100° C. for 16 hours. After being cooled to roomtemperature, the reaction mixture was adjusted to pH 9 with a saturatedaqueous solution of potassium carbonate and exacted with dichloromethane(200 mL×3). The combined organic layers were dried over sodium sulfate,and concentrated in vacuo. The residue was purified by preparative HPLCto afford 2.6 mg of the product (yield was 2.8%). MS obsd. (ESI⁺)[(M+H)⁺] 437, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.10-8.08 (d, J=7.6 Hz, 1H), 8.01 (s, 1 H), 7.85-7.83 (d, J=7.6 Hz, 1 H), 7.76-7.71 (m, 2 H),7.60-7.58 (m, 2 H), 5.92 (s, 1 H), 5.31 (s, 2 H), 4.51 (s, 2 H),4.22-3.97 (m, 4 H), 3.75-3.73 (d, J=8 Hz, 2 H), 2.47 (s, 3 H), 3.11-3.08(m, 2 H), 2.47-2.31 (m, 2 H), 1.63 (s, 3 H).

Example 65N-[(3-Aminooxetan-3-yl)methyl]-2-(9-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

A mixture ofN-[(3-aminooxetan-3-yl)methyl]-2-(9-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(20 mg, 0.044 mmol, prepared in analogy to Example 1-4) and sodiummethoxide (24 mg, 0.44 mmol) in methanol (2 mL) was heated with stirringin a sealed 5 mL of microwave process via for 20 minutes at 100° C.under microwave irradiation. The resulting mixture was concentrated invacuo. The residue was purified by preparative HPLC to afford 6 mg ofthe product (yield was 29%). MS obsd. (ESI⁺) [(M+H)⁺] 469, ¹H NMR (400MHz, CD₃OD) δ ppm 7.67 (s, 1 H), 7.62-7.52 (m, 1 H), 7.47 (d, J=8.59 Hz,1 H), 7.41 (d, J=7.07 Hz, 1 H), 7.31 (dd, J=8.46, 1.89 Hz, 1 H), 7.16(d, J=7.83 Hz, 1 H), 5.99 (s, 1 H), 5.08 (s, 2 H), 4.63-4.49 (m, 4 H),4.31 (t, J=5.56 Hz, 2 H), 3.98-3.81 (m, 5 H), 3.54 (s, 2 H), 2.43 (s, 3H).

Example 664-(4-{[(3-Aminooxetan-3-yl)methyl]amino}-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepin-7-ol1,1-dioxide

A mixture ofN-[(3-aminooxetan-3-yl)methyl]-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(20 mg, 0.044 mmol, prepared in analogy to Example 1-5), potassiumhydroxide (24 mg, 0.44 mmol) in dimethylsulfoxide (2 mL) was heated withstirring in a sealed 5 mL of microwave process via for 20 minutes at100° C. under microwave irradiation. The resulting mixture was purifiedby preparative HPLC to afford 6 mg of the product (yield was 30%). MSobsd. (ESI⁺) [(M+H)⁺] 455, ¹HNMR (400 MHz, CD₃OD) δ ppm 7.77 (d, J=8.59Hz, 1 H), 7.67 (s, 1 H), 7.45 (d, J=8.59 Hz, 1 H), 7.31 (dd, J=8.46,1.64 Hz, 1 H), 7.18 (d, J=2.53 Hz, 1 H), 6.72 (dd, J=8.59, 2.27 Hz, 1H), 6.19 (s, 1 H), 5.03 (s, 2 H), 4.68 (d, J=6.57 Hz, 2 H), 4.61 (d,J=6.57 Hz, 2 H), 3.66 (s, 2 H), 3.50 (brs, 2 H), 3.30 (m, 2 H), 2.43 (s,3 H).

Example 673-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropane-1,2-diol

2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(2-methylprop-2-en-1-yl)quinolin-4-amine

A solution of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (372.0 mg, 1.0 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and 2-methylprop-2-en-1-amine (213.0 mg,3.0 mmol) in 1-methyl-2-pyrrolidinone (1.0 mL) was heated with stirringat 160° C. for 36 hours. The reaction mixture was cooled to roomtemperature, diluted with water (10 mL) and extracted with ethyl acetate(100 mL). The organic layer was washed with brine (50 mL×2), dried overanhydrous sodium sulfate and then concentrated in vacuo to afford 407.0mg of the product as a light yellow solid. MS obsd. (ESI⁺) [(M+H)⁺] 408.

3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropane-1,2-diol

A mixture solution of2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(2-methylprop-2-en-1-yl)quinolin-4-amine(200.0 mg, 0.49 mmol), 4-methylmorpholine N-oxide monohydrate (67.2 mg,0.58 mmol) and osmium tetroxide (6.4 mg, 0.024 mmol) in acetone (10 mL)was stirred at room temperature for 1 hour. After being quenched byadding sodium bisulfite, the resulting mixture was extracted with ethylacetate (100 mL). The organic layer was washed with brine (50 mL×2),dried over anhydrous sodium sulfate and then concentrated in vacuo. Theresidue was purified by preparative HPLC to afford 25.1 mg of thedesired product as a light yellow solid (yield was 11.6%), MS obsd.(ESI⁺) [(M+H)⁺] 442, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.96 (dd, J=7.83,1.01 Hz, 1 H), 7.89 (d, J=7.33 Hz, 1H), 7.60 (td, J=7.45, 1.26 Hz, 1 H),7.54 (s, 1 H), 7.50-7.34 (m, 2 H), 7.28 (dd, J=8.59, 1.77 Hz, 1 H), 6.22(s, 1 H), 5.13 (brs, 2 H), 4.52 (brs, 2 H), 3.66-3.46 (m, 4 H), 3.40 (s,2 H), 3.33 (dt, J=3.28, 1.64 Hz, 2 H), 2.41 (s, 3 H), 1.31 (s, 3 H).

Example 684-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}butane-1,3-diol

A solution of4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-3-hydroxybutanoicacid (50.0 mg, 0.11 mmol, prepared in analogy to Example 11-3), sodiumborohydride (100.0 g, 2.6 mmol) and iodine (300.0 mg, 1.2 mmol) intetrahydrofuran (10.0 mL) was stirred at room temperature for 16 hours.The reaction mixture was diluted with water (20 mL) and extracted withethyl acetate (100 mL). The organic layer was washed with brine (50mL×2), dried over anhydrous sodium sulfate and then concentrated invacuo. The residue was purified by preparative HPLC to afford 20.0 mg ofthe desired product as a light yellow solid (yield was 41.2%). MS obsd.(ESI⁺) [(M+H)⁺] 442, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.04 (d, J=7.58 Hz, 1H), 7.90 (d, J=7.58 Hz, 1 H), 7.81 (brs, 1 H), 7.75-7.59 (m, 2 H),7.59-7.41 (m, 2 H), 6.10 (s, 1 H), 5.25 (brs, 2 H), 4.53 (brs, 2 H),4.12 (brs, 1 H), 3.82 (t, J=5.94 Hz, 2 H), 3.68 (brs, 2 H), 3.55 (dd,J=13.77, 4.17 Hz, 1 H), 3.44 (dd, J=13.64, 7.33 Hz, 1 H), 2.45 (s, 3 H),1.97-1.73 (m, 2 H).

Example 69-1N-[6-Methyl-2-(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine

4-(4-Chloro-6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

To a cooled solution of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (186 mg, 0.5 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) in dry tetrahydrofuran (10 mL) was addedn-butyllithium (0.47 mL, 1.6 N) at −78° C. under argon. After beingstirred at −78° C. for 1 hour, a solution of methyl iodide in drytetrahydrofuran (5 mL) was added to the reaction mixture dropwise at−78° C. Then the mixture was stirred overnight whilst allowing thetemperature to rise slowly to room temperature. The resulting reactionmixture was poured into a saturated aqueous solution of ammoniumchloride (20 mL) and extracted with ethyl acetate (50 mL). The organiclayer was dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by flash column chromatography (eluting with 20%ethyl acetate in petroleum ether) to afford the desired product.

N-[6-Methyl-2-(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 30by using4-(4-chloro-6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and ethane 1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.01 (d, J=7.83 Hz, 1 H), 7.85 (brs, 1 H),7.70-7.60 (m, 2 H), 7.52-7.40 (m, 2 H), 7.30 (dd, J=8.59, 1.77 Hz, 1 H),6.03 (s, 1 H), 5.13 (brs, 2 H), 3.67-3.57 (m, 1 H), 3.56-3.48 (m, 2 H),3.31-3.30 (m, 3 H), 3.15-3.04 (m, 2 H), 2.42 (s, 3 H), 1.51 (brs, 2 H).

Example 69-2N-[(3-Aminooxetan-3-yl)methyl]-6-methyl-2-(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 69-1 in Scheme 30by using4-(4-chloro-6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺]453, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.01 (d, J=7.83 Hz, 1 H), 7.92 (brs,1 H), 7.66 (s, 2 H), 7.52-7.41 (m, 2 H), 7.30 (dd, J=8.59, 1.77 Hz, 1H), 6.19 (s, 1 H), 5.18 (brs, 1 H), 5.10 (brs, 1 H), 4.66-4.55 (m, 4 H),3.68 (d, J=2.02 Hz, 2 H), 3.65-3.57 (m, 1 H), 3.35-3.30 (m, 3 H), 2.43(s, 3 H), 1.60-1.40 (brs, 2 H).

Example 70N-[(3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}oxetan-3-yl)methyl]-2,2,2-trifluoroacetamide

A solution of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (500 mg, 1.341 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1),N-[(3-aminooxetan-3-yl)methyl]-2,2,2-trifluoroacetamide (570 mg, 70%,2.01 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride(99 mg, 0.134 mmol), 1,1′-bis(diphenylphosphino)ferrocene (75 mg, 0.134mmol), and sodium tert-butoxide (258 mg, 2.682 mmol) in 1,4-dioxane (8mL) was heated with stirring in a sealed 10 mL of microwave process vialfor 1.5 hours at 120° C. under microwave irradiation. The reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate and concentrated in vacuo.The residue was purified by flash column chromatography (eluting with1-10% methanol in dichloromethane) to afford 190 mg of the desiredproduct (yield was 26%). MS obsd. (ESI⁺) [(M+H)⁺] 535, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.98 (m, 1 H), 7.82 (d, J=6.8 Hz, 1 H), 7.66 (s, 1 H), 7.59(td, J=0.8, 7.6 Hz, 1 H), 7.47-7.42 (m, 2 H), 7.32 (dd, J=1.6, 8.8 Hz, 1H), 5.70 (s, 1 H), 5.18 (s, 2 H), 4.86 (m, 4 H), 4.52 (s, 2 H), 3.87 (s,2 H), 3.60 (t, J=4.8 Hz, 2 H), 2.43 (s, 3 H).

Example 71N-[3-(Aminomethyl)oxetan-3-yl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

To a solution ofN-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}oxetan-3-yl)methyl]-2,2,2-trifluoroacetamide(190 mg, 0.355 mmol) in methanol (15 mL) was added an aqueous solutionof potassium carbonate (197 mg, 1.42 mmol, dissolved in 2 mL of water).After being stirred at room temperature overnight, the resulting mixturewas concentrated in vacuo to remove methanol. The residue was dilutedwith water (5 mL) and extracted with dichloromethane (15 mL). Theorganic layer was dried over sodium sulfate and concentrated in vacuo.The residue was purified by preparative HPLC to give 23 mg of thedesired product as a white solid (yield was 14.8%). MS obsd. (ESI⁺)[(M+H)⁺] 439, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98-7.96 (m, 1 H),7.58-7.56 (d, J=6.8 Hz, 1 H), 7.44-7.40 (m, 2 H), 7.32-7.30 (t, 1 H),7.19 (m, 2 H), 5.99 (s, 1 H), 5.54 (s, 1 H), 4.98-4.97 (d, J=6.0, 4 H),4.64-4.63 (m, 3 H), 3.51 (s, 2 H), 3.30 (s, 2 H), 2.34 (s, 3 H).

Example 722-(Aminomethyl)-2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,3-diol

A mixture ofN-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}oxetan-3-yl)methyl]-2,2,2-trifluoroacetamide(269 mg, 0.503 mmol) and a solution of ammonia in methanol (7 M, 10 mL,)was stirred at room temperature overnight. The resulting mixture wasconcentrated in vacuo and the residue was purified by preparative HPLCto afford 58 mg of the product as a white solid (yield was 25%). MSobsd. (ESI⁺) [(M+H)⁺] 457, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.11-8.09 (t,J=6.4, 1.2 Hz, 1 H), 8.00-7.96 (m, 1 H), 7.86 (s, 1 H), 7.76-7.73 (m, 2H), 7.64-7.60 (m, 2 H), 6.49 (s, 1 H), 5.33 (s, 2 H), 4.55 (s, 2 H),3.82 (s, 2 H), 3.77-3.75 (m, 6 H), 2.49 (s, 3 H).

Example 734-Amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-2-one

To a solution of1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-5-oxopyrrolidine-3-carboxamide(100 mg, 0.22 mmol, byproduct of Example 47-2) in acetonitrile (2 mL)and water (2 mL) was added (diacetoxyiodo)benzene (91 mg, 0.28 mmol).The mixture was stirred at room temperature overnight. The reactionmixture was diluted with water, acidified with concentratedhydrochloride acid (12 N), and extracted with dichloromethane. Theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo. The residue was purified by column chromatography on silicagel (eluting with 1-10% methanol in dichloromethane) to give 10 mg ofthe product as a white solid. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR (400MHz, DMSO-d6) δ ppm 7.94-7.87 (m, 2 H), 7.60 (td, J=1.2, 7.2 Hz, 1 H),7.55 (d, J=8.8 Hz, 1 H), 7.47-7.43 (m, 2 H), 7.37 (dd, J=2.0, 8.8 Hz, 1H), 7.22 (s, 1 H), 5.13 (s, 2 H), 4.42 (brs, 2 H), 4.02 (dd, J=2.0, 9.6Hz, 1 H), 3.87 (td, J=3.6, 6.8 Hz, 1 H), 3.62 (dd, J=4.8, 9.6 Hz, 2 H),3.45 (dd, J=3.2, 9.6 Hz, 1 H), 3.14-3.13 (m, 1 H), 2.85 (dd, J=7.2, 16.8Hz, 1 H), 2.36 (s, 3 H).

Example 742-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(methylsulfinyl)ethyl]quinolin-4-amine

2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(methylsulfanyl)ethyl]quinolin-4-amine

A dried microwave process vial capped with a rubber septum was purgedwith argon and charged with tris(dibenzylideneacetone)dipalladium(0)(2.88 mg, 0.005 mmol),1-(N,N-dimethylamino)-1′-(dicyclohexylphosphino)biphenyl (5.90 mg, 0.015mmol) and sodium tert-butoxide (134 mg, 1.4 mmol). The tube was purgedwith argon, and a solution of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (370 mg, 1.0 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and 2-(methylthio)ethylamine (128 mg, 1.4mmol) in 1,4-dioxane (2.0 mL) was added. The mixture was heated withstirring in a sealed 5 mL of microwave process vial for 2 hour at 120°C. under microwave irradiation. After being cooled to room temperature,the reaction mixture was diluted with ethyl acetate, filtered throughcelite and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (eluting with 1-10% methanol indichloromethane) to afford 341 mg of the desired product (yield was80%). MS obsd. (ESI⁺) [(M+H)⁺] 428.

2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(methylsulfinyl)ethyl]quinolin-4-amine

To a solution of2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(methylsulfanyl)ethyl]quinolin-4-amine(300 mg, 0.70 mmol) in acetic acid (2 mL) was added hydrogen peroxide(0.5 mL) at room temperature. The mixture was stirred at roomtemperature for 2 hours. The resulting mixture was diluted with ethylacetate (10 mL), washed with a saturated aqueous solution of sodiumbicarbonate, dried over sodium sulfate, and concentrated in vacuo. Theresidue was purified by preparative HPLC to afford the desired product.MS obsd. (ESI⁺) [(M+H)⁺] 444, ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d,J=7.07 Hz, 1 H), 7.88 (dd, J=7.83, 1.26 Hz, 1 H), 7.70-7.60 (m, 2 H),7.47 (td, J=7.64, 1.14 Hz, 1 H), 7.34 (d, J=8.34 Hz, 1 H), 7.25 (dd,J=8.34, 1.52 Hz, 1 H), 6.98 (t, J=5.56 Hz, 1 H), 6.14 (s, 1 H), 5.09(brs, 2 H), 4.5 (brs, 2 H), 3.81-3.56 (m, 4 H), 3.20-3.07 (m, 1 H),3.04-2.92 (m, 1 H), 2.65 (s, 3 H), 2.35 (s, 3 H).

Example 75N-{2-[(2-Aminoethyl)sulfonyl]ethyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

To a solution ofN-{2-[(2-aminoethyl)sulfanyl]ethyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine(40 mg, 0.087 mmol, prepared in analogy to Example 3-1 by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and 2-[(2-aminoethyl)sulfanyl]ethylamine) in acetic acid (2mL), potassium permanganate (15 mg, 0.08 mmol) was added. After beingstirred at room temperature for 30 minutes, the mixture was concentratedin vacuo. The residue was purified by preparative HPLC to afford thepure product as a solid. MS obsd. (ESI⁺) [(M+H)⁺] 489, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.99 (dd, J=7.83, 1.26 Hz, 1 H), 7.93 (d, J=7.58 Hz, 1 H),7.65 (td, J=7.45, 1.26 Hz, 1 H), 7.54 (s, 1 H), 7.49-7.41 (m, 2 H), 7.30(dd, J=8.46, 1.64 Hz, 1 H), 6.13 (s, 1 H), 5.16 (s, 2 H), 4.63 (brs, 1H), 4.56 (brs, 1 H), 3.91 (t, J=6.82 Hz, 2 H), 3.60 (t, J=4.67 Hz, 2 H),3.55-3.45 (m, 2 H), 3.31-3.27 (m, 2 H), 3.20-3.06 (m, 2 H), 2.41 (s, 3H).

Example 76N-[2-(1-Imino-1-oxido-1,2,3,5-tetrahydro-4H-1lambda˜4˜,4-benzothiazepin-4-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine

N-[4-(4-Chloro-6-methylquinolin-2-yl)-1-oxido-2,3,4,5-tetrahydro-1H-1lambda˜4˜,4-benzothiazepin-1-ylidene]-2,2,2-trifluoroacetamide

To a suspension of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (357 mg, 1.0 mmol, prepared in analogy to the one in Example18-1), trifluoroacetamide (226 mg, 2.0 mmol), magnesium oxide (160 mg,4.0 mmol) and rhodium(II) acetate (11 mg, 2.5 mol) in dichloromethane(10 mL) was added (diacetoxyiodo)benzene (483 mg, 1.5 mmol). After beingstirred at room temperature overnight, the resulting mixture wasconcentrated in vacuo. The residue was purified by flash columnchromatography (eluting with 20-33% ethyl acetate in petroleum ether) toafford 234 mg of the pure product (yield was 50%). MS obsd. (ESI⁺)[(M+H)⁺] 468.

4-(4-Chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1H-1lambda˜4˜,4-benzothiazepin-1-imine1-oxide

To a solution ofN-[4-(4-chloro-6-methylquinolin-2-yl)-1-oxido-2,3,4,5-tetrahydro-1H-1lambda˜4˜,4-benzothiazepin-1-ylidene]-2,2,2-trifluoroacetamide(234 mg, 0.50 mmol) in methanol (10 mL) was added potassium carbonate(690 mg, 5.0 mmol). After being stirred at room temperature for 30minutes, the reaction mixture was concentrated in vacuo. The residue waspurified by column chromatography (eluting with 20-33% ethyl acetate inpetroleum ether) to afford the N-unsubstituted sulfoximines. MS obsd.(ESI⁺) [(M+H)⁺] 372.

N-[2-(1-Imino-1-oxido-1,2,3,5-tetrahydro-4H-1lambda˜4˜,4-benzothiazepin-4-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 9-1 in Scheme 35by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1H-1lambda˜4˜,4-benzothiazepin-1-imine1-oxide and ethane 1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 396, ¹H NMR(400 MHz, DMSO-d6) δ ppm 7.91 (d, J=8.08 Hz, 1 H), 7.83 (d, J=7.58 Hz, 1H), 7.70 (s, 1 H), 7.58-7.52 (m, 1 H), 7.44-7.37 (m, 1 H), 7.30 (d,J=8.59 Hz, 1 H), 7.21 (dd, J=8.46, 1.64 Hz, 1 H), 6.63 (t, J=5.43 Hz, 1H), 6.01 (s, 1 H), 5.11 (brs, 2 H), 4.61 (brs, 1 H), 4.10 (brs, 1 H),3.49-3.36 (m, 2 H), 3.31 (q, J=6.23 Hz, 3 H), 2.86-2.76 (m, 3 H), 2.34(s, 3 H).

Example 772-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(S-methylsulfonimidoyl)ethyl]quinolin-4-amine

The title compound was prepared in analogy to Example 76 in Scheme 33 byusing2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(methylsulfinyl)ethyl]quinolin-4-amine(prepared in analogy to Example 74) and trifluoroacetamide. MS obsd.(ESI⁺) [(M+H)⁺] 459, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.04 (d, J=7.33 Hz, 1H), 7.96 (d, J=7.33 Hz, 1 H), 7.73-7.66 (m, 2 H), 7.60-7.55 (m, 1 H),7.52 (s, 1 H), 7.46-7.40 (m, 1 H), 6.17 (s, 1 H), 5.26 (brs, 2 H), 4.50(brs, 2 H), 3.98 (t, J=6.69 Hz, 2 H), 3.68 (brs, 2 H), 3.59 (t, J=6.82Hz, 2 H), 3.14 (s, 3 H), 2.45 (s, 3 H).

Example 78-1trans-4-Amino-1-[2-(1-imino-1-oxido-1,2,3,5-tetrahydro-4H-1lambda˜4˜,4-benzothiazepin-4-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1H-1lambda˜4˜,4-benzothiazepin-1-imine1-oxide (100 mg, 0.27 mmol), tert-butyl(trans-4-hydroxypyrrolidin-3-yl)carbamate (164 mg, 0.81 mmol) andn-butanol (0.2 mL) was stirred at 160° C. overnight. After the mixturebeing cooled to room temperature, to the above mixture was addeddichloromethane (10 mL) and trifluoroacetic acid (10 mL). The mixturewas stirred further until the reaction finished monitoring by TLC, andthen concentrated in vacuo. The residue was dissolved in dichloromethaneand the solution was washed with an aqueous solution of sodium hydroxide(10% W/W) and brine, dried over sodium sulfate, and concentrated invacuo. The residue was purified by preparative HPLC to afford theproduct as a solid. MS obsd. (ESI⁺) [(M+H)⁺] 438, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.05 (d, J=7.83 Hz, 1 H), 7.84 (s, 1 H), 7.81 (s, 1 H),7.61 (t, J=7.45 Hz, 1 H), 7.52 (d, J=8.59 Hz, 1 H), 7.49-7.43 (m, 1 H),7.36-7.30 (m, 1 H), 6.14 (s, 1 H), 5.31-5.16 (m, 2 H), 4.25 (brs, 1 H),4.17-4.05 (m, 1 H), 4.05-3.94 (m, 1 H), 3.62 (d, J=10.61 Hz, 2 H),3.70-3.58 (m, 2 H), 3.57-3.41 (m, 3 H), 2.43 (s, 3 H).

Example 78-2trans-1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-fluoropyrrolidin-3-amine

The title compound was prepared in analogy to Example 78-1 in Scheme 7by using4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and tert-butyl (trans-4-fluoropyrrolidin-3-yl)carbamate. MSobsd. (ESI⁺) [(M+H)⁺] 441, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (dd,J=7.71, 1.89 Hz, 1 H), 7.91-7.75 (m, 2 H), 7.62 (t, J=7.45 Hz, 1 H),7.52 (d, J=8.59 Hz, 1 H), 7.45 (td, J=7.58, 3.28 Hz, 1 H), 7.32 (d,J=8.59 Hz, 1 H), 6.19 (s, 1 H), 5.18 (brs, 2 H), 5.06 (m, 1 H), 4.53(brs, 2 H), 4.17 (m, 1 H), 4.03 (dd, J=9.98, 5.43 Hz, 1 H), 3.81-3.54(m, 4 H), 3.45-3.35 (m, 1 H), 2.42 (s, 3 H).

Example 791-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3-carboxamide

1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3-carboxylicacid

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (500 mg, 1.34 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and methylpyrrolidine-3-carboxylate (173mg, 1.34 mmol) and N,N-diisopropylethylamine (346 mg, 2.68 mmol) washeated with stirring in a sealed 10 mL of microwave process vial for 1.5hours at 140° C. under microwave irradiation. The resulting mixture waspurified by preparative HPLC to afford 120 mg of the pure product (yieldwas 19.8%).

1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3-carbonylchloride

To a cooled solution of1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3-carboxylicacid (120 mg, 0.26 mmol) in dichloromethane (20 mL) was added two dropsof N,N-dimethylformamide followed by oxalyl chloride (30.6 μL, 0.39mmol) at 0° C. After being stirred for 16 hours at room temperature, thereaction mixture was concentrated in vacuo to afford 100 mg of the crudeproduct which was used for the next step without any furtherpurification.

1-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3-carboxamide

To a cooled solution of1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3-carbonylchloride (100 mg, 0.21 mmol) in dichloromethane (20 mL) was added asaturated solution of ammonia in dichloromethane (10 mL) slowly at 0° C.After being stirred for 16 hours at room temperature, the mixture wasconcentrated in vacuo. The residue was purified by preparative HPLC toafford 13 mg of the desired product (yield was 13.5%). MS obsd. (ESI⁺)[(M+H)⁺] 451, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.08-8.05 (m, 2 H),7.33-7.31 (d, J=7.6 Hz, 1 H), 7.70-7.67 (m, 2 H), 7.57-7.55 (m, 2 H),5.85 (s, 1 H), 5.25 (s, 2 H), 4.5 (s, 2 H), 4.03-3.94 (m, 4 H), 3.71 (s,2 H), 3.29-3.21 (m, 1 H), 2.45 (s, 3 H), 2.41-2.32 (m, 1 H), 2.31-2.21(m, 1 H).

Example 80N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(methylsulfinyl)quinolin-4-yl]propane-1,3-diamine

4-[4-Chloro-6-(methylsulfinyl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

To a cooled solution of4-[4-Chloro-6-(methylsulfanyl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (800 mg, 1.98 mmol, prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) in dichloromethane (70 mL) was added asolution of 3-chloroperoxybenzoic acid (400 mg, 198 mmol, purity 85%) indichloromethane (30 mL) dropwise at 0° C. After being stirred at 0° C.for 20 minutes, the reaction mixture was washed with a saturated aqueoussolution of sodium bicarbonate (100 mL), a saturated aqueous solution ofsodium thiosulphate (100 mL×3) and brine (100×2). The organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo to afford500 mg of the desired product (yield was 60%).

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(methylsulfinyl)quinolin-4-yl]propane-1,3-diamine

A mixture of4-[4-chloro-6-(methylsulfinyl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (300 mg, 0.71 mmol) and propane-1,3-diamine (67525 mg, 7.1mmol) was heated with stirring in a sealed 10 mL of microwave processvial for 1 hour at 150° C. under microwave irradiation. The reactionmixture was purified by preparative HPLC to afford the trifluoroaceticacid salt of the desired product. The trifluoroacetic acid salt wasflashed through SPE column with methanol. The eluent was concentrated invacuo and dried by lyopylization to afford 256.8 mg of the desiredproduct (yield was 78%). MS obsd. (ESI⁺) [(M+H)⁺] 459, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.44 (s, 1 H), 8.05-7.96 (m, 3 H), 7.88 (d, J=7.6 Hz, 1 H),7.71 (t, J=7.6 Hz, 1 H), 7.55 (t, J=7.6 Hz, 1 H), 6.02 (s, 1 H), 5.33(s, 2 H), 4.54 (s, 2 H), 3.74 (s, 2 H), 3.61 (t, J=6.0 Hz, 2 H), 3.11(t, J=8.0 Hz, 2 H), 2.82 (s, 3 H), 2.16-2.09 (m, 2 H).

Example 814-[(3-Aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxamide

4-Chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxamide

To a mixture of methyl4-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate(400 mg, 1.04 mmol, prepared in analogy to4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepinein Example 1-1) in tetrahydrofuran (5 mL) and a saturated solution ofammonia in methanol (30 mL) was heated with stirring for 16 hours at120° C. in a sealed tube. The reaction mixture was concentrated in vacuoto afford 300 mg of the product (yield was 78%).

4-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxamide

To a cooled solution of4-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxamide(300 mg, 0.81 mmol) in dichloromethane (50 mL) was added3-chloroperoxybenzoic acid (418 mg, 70% purity, 1.70 mmol) at 0° C.After being stirred for 2 hours at 0° C., the reaction mixture waswashed with a saturated aqueous solution of sodium thiosulphate (50 mL),dried over sodium sulfate, and concentrated in vacuo to afford 300 mg ofthe crude product.

4-[(3-Aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxamide

A mixture of 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxamide (300 mg, 0.75 mmol) andpropane-1,3-diamine (306 mg, 4.14 mmol) was heated with stirring in asealed 10 mL of microwave process vial for 1 hour at 120° C. undermicrowave irradiation. The reaction mixture was purified by preparativeHPLC to afford 23.5 mg of the desired product (yield was 7.2%). MS obsd.(ESI⁺) [(M+H)⁺] 440, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.70-8.69 (d, J=1.6Hz, 1 H), 8.18-8.15 (m, 1 H), 8.10-8.08 (dd, J=1.2, 7.6 Hz, 1 H),7.88-7.84 (t, J=6.8 Hz, 2 H), 7.73-7.72 (m, 1 H), 7.60-7.59 (m, 1 H),6.01 (s, 1 H), 5.34 (s, 2 H), 4.55 (s, 2 H), 3.75 (s, 2 H), 3.64-3.60(t, J=6.8 Hz, 1 H), 3.11-3.09 (m, 2 H), 2.18-2.09 (m, 2 H).

Example 821-{4-[(3-Aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}ethanol

4-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carbaldehyde

To a solution of oxalyl dichloride (36.3 mg, 0.29 mmol) indichloromethane (10 mL) was added a solution of dimethyl sulphoxide (0.1mL, 0.57 mmol) in dichloromethane (10 mL) at −78° C. dropwise. After themixture being stirred for 10 minutes at −78° C., a solution of4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanol(100 mg, 0.26 mmol, prepared in analogy to the one in Example 3-23) indichloromethane (5 mL) was added dropwise. After the mixture beingstirred for further 1 hour at −78° C., triethylamine (0.2 mL, 1.3 mmol)was. The resulting mixture was stirred at −78° C. for 1 hour and then atroom temperature for further 1 hour. The reaction was washed with brine,dried over sodium sulfate and concentrated in vacuo to afford 70 mg ofthe product.

1-[4-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]ethanol

To a cooled solution of4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinoline-6-carbaldehyde(100 mg, 0.26 mmol) in tetrahydrofuran (20 mL) was added a solution ofmethyl magnesium bromide in tetrahydrofuran (0.13 mL, 0.39 mmol, 3 M) at0° C. dropwise. After being stirred for 20 minutes at the temperaturebelow 12° C., the mixture was concentrated in vacuo. The residue waspurified by preparative TLC to give 100 mg of the desired product (yieldwas 96%).

1-{4-[(3-Aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}ethanol

A mixture of1-[4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]ethanol(150 mg, 0.387 mmol) and propane-1,3-diamine (55 mg, 0.74 mmol) washeated with stirring in a sealed 0.5 mL of microwave process vial for1.5 hours at 150° C. under microwave irradiation. The reaction mixturewas purified by preparative HPLC and SPE to afford 70.2 mg of thedesired product (yield was 41.2%). MS obsd. (ESI⁺) [(M+H)⁺] 441, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.10-8.05 (m, 2 H), 7.86-7.80 (d, J=7.6 Hz, 1 H),7.78-7.75 (m, 2 H), 7.72-7.62 (t, J=1.2 Hz, 1 H), 7.60-7.50 (t, J=1.2Hz, 1 H), 5.94 (s, 1 H), 5.30 (s, 2 H), 4.98-4.92 (m, 1 H), 4.58-4.45(m, 2 H), 3.78-3.70 (t, J=2.8 Hz, 2 H), 3.62-3.53 (t, J=4.4 Hz, 2 H),3.10-3.02 (t, J=6.8 Hz, 2 H), 2.12-2.02 (m, 2 H), 1.50-1.40 (d, J=6.4Hz, 3 H).

Example 833-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propanenitrile

A flask containing4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (500 mg, 1.34 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1), 3-aminopropionitrile (140 mg, 2.01 mmol),tris(dibenzylideneacetone)dipalladium(0) (61.8 mg, 0.068 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (83.3 mg, 0.134 mmol),sodium tert-butoxide (257 mg, 2.68 mmol) and toluene (15 ml) wasevacuated and then filled with nitrogen (balloon). After being stirredat 110° C. overnight, the resulting mixture was diluted with water (15mL), and extracted with ethyl acetate (15 mL×4). The combined organiclayers were dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by flash column chromatography (eluting with 10%methanol in dichloromethane) to afford 380 mg of the product as a whitesolid (yield was 70%). MS obsd. (ESI⁺) [(M+H)⁺] 407, ¹H NMR (400 MHz,CD₃OD) δ ppm 8.02-8.00 (m, 1 H), 7.90 (d, J=7.2 Hz, 1 H), 7.69-7.63 (m,2 H), 7.51-7.45 (m, 2 H), 7.34-7.31 (m, 1 H), 6.10 (s, 1 H), 5.19 (s, 2H), 4.55 (brs, 2 H), 3.73 (t, J=13.2 Hz, 2 H), 3.63 (t, J=10 Hz, 2 H),2.85 (t, 2 H), 2.44 (s, 3 H).

Example 842-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(1H-tetrazol-5-yl)ethyl]quinolin-4-amine

A mixture of3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propanenitrile(100 mg, 0.25 mmol), sodium azide (48 mg, 0.98 mmol), dimethyl formamide(2 ml) and ammonium chloride (52.6 mg, 0.98 mmol) was heated at 80° C.in an oil bath overnight. The resulting mixture was diluted with waterand extracted with dichloromethane (10 mL×3). The combined organiclayers were washed with brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by flash columnchromatography (eluting with 10% methanol in dichloromethane) to afford20 mg of the desired product as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]450, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.06 (m, 1 H), 7.92 (t, 1 H), 7.86(s, 1 H), 7.60 (m, 1 H), 7.58-7.52 (m, 3 H), 5.89 (s, 1 H), 5.27 (s, 2H), 4.52 (brs, 2 H), 3.86 (t, 2 H), 3.72 (t, 2 H), 3.33 (t, 2 H), 2.47(s, 3 H).

Example 85N^(˜)4^(˜)-(2-Aminoethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-4,6-diamine

To a solution ofN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-nitroquinolin-4-yl]ethane-1,2-diamine(50 mg, 0.11 mmol, prepared in analogy toN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-1,2-diaminein Example 9-11) in methanol (20 mL) was added tin(II) chloride (102.8mg, 0.55 mmol). After being refluxed overnight, the resulting mixturewas cooled to room temperature, diluted with dichloromethane, washedwith brine, dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified by preparative HPLC to afford 11 mg ofthe desired product (yield was 25%). MS obsd. (ESI⁺) [(M+H)⁺] 398, ¹HNMR (400 MHz, CD₃OD) δ ppm 7.95 (d, J=8.08 Hz, 1 H), 7.79 (d, J=7.58 Hz,1 H), 7.60 (t, J=7.45 Hz, 1 H), 7.47-7.37 (m, 1 H), 7.35 (d, J=8.84 Hz,1 H), 7.06-6.95 (m, 2 H), 6.00 (s, 1 H), 5.10 (s, 2 H), 3.56 (brs, 2 H),3.41 (t, J=6.44 Hz, 2 H), 2.96 (t, J=6.44 Hz, 2 H), 1.29 (brs, 2 H).

Example 865-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-5,7-diazaspiro[3.4]octan-6-one

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (372 mg, 1.0 mmol, prepared in analogy to the one in Example17-1), tert-butyl [(3-aminooxetan-3-yl)methyl]carbamate (202 mg, 1.0mmol), tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.10 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (62 mg, 0.10 mmol) andsodium tert-buoxide (192 mg, 2.0 mmol) in toluene (10 mL) was heated at110° C. overnight. The resulting mixture was diluted with water (20 mL),and extracted with dichloromethane (20 mL×3). The combined organiclayers were washed with brine (50 mL), dried over sodium sulfate, andconcentrated in vacuo. The residue was purified by preparative HPLC toafford 15 mg of the title compound. MS obsd. (ESI⁺) [(M+H)⁺] 465, ¹H NMR(400 MHz, DMSO-d6) δ ppm 8.15 (s, 1 H), 7.98-7.96 (d, J=7.2 Hz, 1 H),7.90-7.87 (m, 1 H), 7.68-7.64 (m, 1 H), 7.53-7.46 (m, 2 H), 7.37-7.34(m, 2 H), 7.17 (s, 1 H), 5.14 (s, 2 H), 4.80-4.74 (m, 4 H), 4.44 (s, 2H), 4.27 (s, 2 H), 3.66-3.64 (t, J=4.8, 4.4 Hz, 2 H), 2.36 (s, 3 H).

Example 87-13-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]amino}propane-1,2-diol

2-Chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-6-methylquinazolin-4-amine

A solution of 2,4-dichloro-6-methylquinazoline (300.0 mg, 1.4 mmol),triethylamine (0.5 mL) and 2,2-dimethyl-1,3-dioxolane-4-methanamine (0.2mL, 1.5 mmol) in methanol (2.0 mL) was stirred at room temperature for16 hours. The reaction mixture was diluted with ethyl acetate (100 mL),washed with brine (50 mL×2), dried over anhydrous sodium sulfate andthen concentrated in vacuo to afford 431 mg of the crude product as awhite solid. MS obsd. (ESI⁺) [(M+H)⁺] 308.

3-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]amino}propane-1,2-diol

A solution of2-chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-6-methylquinazolin-4-amine(431.2 mg, 1.4 mmol) and triethylamine (0.8 mL),2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (296.1 mg, 1.5 mmol)in N,N-dimethyl-formamide (1.0 mL) was stirred at 160° C. for 4 hours.After being cooled to room temperature, the reaction mixture wasdissolved in methanol (2.0 mL). To the above mixture, concentratedhydrochloric acid (0.5 mL) was added, and the resulting mixture wasstirred at room temperature for 1 hour, and then extracted with ethylacetate (100 mL). The organic layer was washed with brine (50 mL×2),dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by preparative HPLC to afford 59.2 mg of theproduct as a white solid (yield was 10%). MS obsd. (ESI⁺) [(M+H)⁺] 429,¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (dd, J=7.83, 1.01 Hz, 1 H), 7.90 (d,J=7.58 Hz, 1 H), 7.66-7.55 (m, 2 H), 7.50-7.35 (m, 2 H), 7.35-7.28 (m, 1H), 5.21 (brs, 2 H), 4.56 (brs, 2 H), 4.05-3.95 (m, 1 H), 3.86 (dd,J=13.26, 4.42 Hz, 1 H), 3.73-3.56 (m, 3 H), 3.53 (t, J=5.05 Hz, 2 H),2.39 (s, 3 H).

Example 87-23-[6-Chloro-2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl))-quinazolin-4-ylamino]-propane-1,2-diol

The title compound was prepared in analogy to Example 87-1 in Scheme 41by using 2,4,6-trichloroquinazoline,2,2-dimethyl-1,3-dioxolane-4-methanamine and2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI⁺)[(M+H)⁺] 449, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (d, J=7.83 Hz, 1 H),7.95-7.84 (m, 2 H), 7.62 (t, J=7.33 Hz, 1 H), 7.53-7.41 (m, 2 H), 7.37(d, J=8.84 Hz, 1 H), 5.21 (brs, 2 H), 4.61 (brs, 2 H), 4.01 (brs, 1 H),3.85 (brs, 1 H), 3.65 (brs, 3 H), 3.52 (t, J=4.67 Hz, 3 H).

Example 88-1N-[2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]ethane-1,2-diamine

tert-Butyl {2-[(2-chloro-6-methylquinazolin-4-yl)amino]ethyl}carbamate

A mixture of 2,4-dichloro-6-methylquinazoline (700 mg, 3.29 mmol),tert-butyl N-(2-aminoethyl)carbamate (2.6 g, 16.4 mmol) and methanol (35mL) was stirred at room temperature for 1 hour. The resulting mixturewas concentrated in vacuo and the residue was purified by flash columnchromatography to afford 1.0 g of the product as a white solid (yieldwas 91%).

tert-Butyl{2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]aminoethyl}carbamate

To a solution of tert-butyl{2-[(2-chloro-6-methylquinazolin-4-yl)amino]ethyl}carbamate (460 mg,1.366 mmol) in n-butanol (6 mL) was added2,3,4,5-tetrahydro-1,4-benzothiazepine (248 mg, 1.50 mmol) andtriethylamine (276 mg, 2.732 mmol). The mixture was heated with stirringat 100° C. in a sealed tube for 4 hours, and then concentrated in vacuo.The residue was purified by flash column chromatography to afford 350 mgof the desired product as a white solid (yield was 55%).

N-[2-(2,3-Dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]ethane-1,2-diamine

To a cooled solution of trifluoroacetic acid in dichloromethane (2 mL,V/V=1/4) was added tert-butyl{2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]aminoethyl}carbamate(120 mg, 0.258 mmol) in an ice bath. The mixture was stirred for 3 hourswhilst allowing the temperature of the mixture rising naturally to roomtemperature, and then concentrated in vacuo. The residue was dissolvedin water (10 mL), and washed with dichloromethane (10 mL). The aqueouslayer was adjusted to pH 10 with a saturated aqueous solution of sodiumcarbonate and extracted with ethyl acetate (20 mL×2). The organicextracts were dried with sodium sulfate, concentrated in vacuo to afford68 mg of the product as a white solid (yield was 72%). MS obsd. (ESI⁺)[(M+H)⁺] 366, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.67-7.64 (t, J=12.0 Hz, 2H), 7.49-7.47 (d, J=8.4 Hz, 1 H), 7.38-7.30 (m, 2 H), 7.23-7.19 (dd,J=8.4, 7.6 Hz, 2 H), 7.13-7.09 (dd, J=8.8 Hz, 1 H), 5.04 (s, 2 H), 4.38(s, 2 H), 3.75-3.72 (m, 2 H), 2.98-2.92 (m, 4 H), 2.39 (s, 3 H).

Example 88-2(1-Amino-cyclopropylmethyl)-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinolin-4-yl]-amine

The title compound was prepared in analogy to Example 88-1 in Scheme 42by using 2,4-dichloro-6-methylquinazoline, tert-butyl[1-(aminomethyl)cyclopropyl]carbamate and2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI⁺) [(M+H)⁺]408, ¹H NMR (400 MHz, CDCl₃) δ ppm 7.766-7.748 (d, J=7.2 Hz, 1 H), 7.632(s, 1 H), 7.410-7.328 (m, 5 H), 5.936 (s, 1 H), 5.333-5.295 (d, J=15.2Hz, 1 H), 4.924 (m, 2 H), 4.400 (s, 1 H), 3.644 (s, 2 H), 3.332 (s, 2H), 2.398 (s, 3 H), 0.740-0.678 (m, 4 H).

Example 89N-[6-Methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]ethane-1,2-diamine

tert-Butyl{2-[2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]aminoethyl}carbamate

To a solution of oxone (120 mg, 0.200 mmol) in water (0.7 mL) which wascooled below 0° C. in an ice bath, was added a solution of tert-butyl{2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]aminoethyl}carbamate(155 mg, 0.333 mmol) in methanol (3 mL) dropwise. The mixture wasstirred below 0° C. about 20 minutes. The formed precipitate wascollected by filtration, washed with water and purified by flash columnchromatography to afford 124 mg of the product as a white solid (yieldwas 77%).

N-[6-Methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 88-1 in Scheme 42by using tert-butyl{2-[2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]aminoethyl}carbamate(150 mg, yield was 86%). MS obsd. (ESI⁺) [(M+H)⁺] 382, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.74-7.72 (t, J=8.0 Hz, 2 H), 7.66-7.62 (d, J=16.0 Hz, 1H), 7.49-7.44 (m, 2 H), 7.42-7.40 (m, 1 H), 7.38-7.33 (m, 1 H),5.29-5.25 (d, J=16.0 Hz, 1 H), 4.81-4.70 (m, 1 H), 4.58-4.51 (m, 1 H),3.79-3.70 (m, 2 H), 3.53-3.34 (m, 4 H), 3.03-3.00 (m, 2 H), 2.40 (s, 3H).

Example 90N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]ethane-1,2-diamine

tert-Butyl{2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]aminoethyl}carbamate

To a solution of tert-butyl{2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]aminoethyl}carbamate(190 mg, 0.408 mmol) in dichloromethane (10 mL) was added dropwise asolution of 3-chloroperbenzoic acid (228.6 mg, 1.02 mmol) indichloromethane (6 mL) in an ice bath. After the mixture being stirredin an ice bath for 2 hours, the reaction was quenched by the addition ofa saturated aqueous solution of sodium thiosulphate. The separatedorganic layer was washed by a saturated aqueous solution of sodiumbicarbonate and brine, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The residue was purified by flash columnchromatography (eluting with 20-40% ethyl acetate in petroleum ether) togive 170 mg of the product.

N-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 88-1 in Scheme 42by using tert-butyl{2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]aminoethyl}carbamate.MS obsd. (ESI⁺) [(M+H)⁺] 398, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.98 (d,J=6.8 Hz, 1 H), 7.83 (d, J=7.6 Hz, 1 H), 7.65 (s, 1 H), 7.61 (dd, J=6.8,7.6 Hz, 1 H), 7.44 (t, J=7.2 Hz, 1 H), 7.38 (dd, J=1.6, 8.4 Hz, 1 H),7.31 (d, J=8.4 Hz, 1 H), 5.20 (s, 2 H), 4.58 (brs, 2 H), 3.73 (t, J=6.4Hz, 2 H), 3.54-3.48 (m, 2 H), 2.97 (t, J=6.4 Hz, 2 H), 2.39 (s, 3 H).

Example 91N-[3-(Aminomethyl)oxetan-3-yl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

2,2,2-Trifluoro-N-[(3-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}oxetan-3-yl)methyl]acetamide

The title compound was prepared as a light white solid in analogy toExample 62-1 in Scheme 23 by using2-chloro-6-methylquinazolin-4(3H)-one,2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide andN-[(3-aminooxetan-3-yl)methyl]-2,2,2-trifluoroacetamide (yield was 80%).

N-[3-(Aminomethyl)oxetan-3-yl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

To a stirred of2,2,2-trifluoro-N-[(3-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}oxetan-3-yl)methyl]acetamide(70 mg, 0.135 mmol) in ethanol (5 mL) was added an aqueous solution ofsodium hydroxide (5 N, 1 mL). After being stirred at room temperatureovernight, the resulting mixture was diluted with water (15 mL), andextracted with dichloromethane (15 mL×3). The organic layers werecombined, washed with brine, dried over sodium sulfate, and concentratedin vacuo. The residue was purified by preparative HPLC to afford 7 mg ofthe desired product as a white solid. MS obsd. (ESI⁺) [(M+H)⁺] 424, ¹HNMR (400 MHz, CD₃OD) δ ppm 7.97 (s, 1 H), 7.83-7.78 (m, 2 H), 7.71-7.68(m, 1 H), 7.61-7.54 (m, 3 H), 5.45 (d, 1 H), 5.15 (brs, 1 H), 4.81-4.74(m, 5 H), 4.51 (brs, 3 H), 3.54 (brs, 2 H), 2.45 (s, 3 H).

Example 92-1N-(trans-4-Fluoropyrrolidin-3-yl)-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

Benzyltrans-3-fluoro-4-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}pyrrolidine-1-carboxylate

A suspension of 6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one (600 mg, 1.77 mmol, prepared in analogy tothe one in Example 91),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(1.02 g, 2.3 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (400 mg, 2.6mmol) in anhydrous N,N-dimethylformamide (10 mL) was stirred at roomtemperature for 10 minutes. Then a solution of benzyltrans-3-amino-4-fluoropyrrolidine-1-carboxylate (500 mg, 2.1 mmol) inN,N-dimethylformamide (5 mL) was added dropwise. After being heated at60° C. overnight, the mixture was diluted with water (50 mL), extractedwith dichloromethane (50 mL). The organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified by flash column chromatography (gradient elutingwith 10% to 25% ethyl acetate in dichloromethane) to afford 415 mg ofthe desired product as a yellow solid (yield was 41.8%).

N-(trans-4-Fluoropyrrolidin-3-yl)-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

A mixture of benzyltrans-3-fluoro-4-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}pyrrolidine-1-carboxylate(200 mg, 0.35 mmol) and an aqueous solution of hydrochloric acid (5 mL,6 N) was refluxed for 6 hours. The resulting mixture was basified byadding an aqueous solution of sodium hydroxide (1 N) to pH 10, and thenextracted with dichloromethane (50 mL). The organic layer was washedwith brine, dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified by preparative HPLC to afford thedesired compound as a yellow solid. MS obsd. (ESI⁺) [(M+H)⁺] 426, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.76 (m, 3 H), 7.45 (m, 4 H), 5.32 (m, 3 H), 4.61(s, 3 H), 3.70-3.11 (m, 6 H), 2.41 (s, 3 H).

Example 92-2N-(trans-4-Fluoropyrrolidin-3-yl)-6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

The title compound was prepared in analogy to Example 92-1 in Scheme 44by using6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one(prepared in analogy to6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-onein Example 91) and benzyltrans-3-amino-4-fluoropyrrolidine-1-carboxylate. MS obsd. (ESI⁺)[(M+H)⁺] 442, ¹H NMR (400 MHz, CDCl₃) δ ppm 8.40-8.02 (d, J=7.6 Hz, 1H), 7.83-7.81 (d, J=7.2 Hz, 1 H), 7.52-7.49 (m, 1 H), 7.37-7.35 (d,J=10.8 Hz, 3 H), 7.22 (s, 1 H), 5.41 (s, 1 H), 5.30-5.00 (brs, 2 H),4.90-4.55 (brs, 2 H), 3.70-3.68 (d, J=5.2 Hz, 1 H), 3.48 (s, 2 H),3.31-3.25 (brs, 2 H) 2.95 (s, 1 H), 2.38 (s, 3 H), 2.20-2.18 (d, J=8.8Hz, 1 H).

Example 93-11-[6-Methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-amine

tert-Butyl{1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-yl}carbamate

The title compound was prepared in analogy to benzyl(3S,4S)-3-fluoro-4-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}pyrrolidine-1-carboxylatein Example 92 by using6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-oneand tert-butyl (pyrrolidin-3-yl)carbamate.

1-[6-Methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-amine

The title compound was prepared in analogy to Example 90 in Scheme 44 byusing tert-butyl{1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-yl}carbamate.MS obsd. (ESI⁺) [(M+H)⁺] 408, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.73 (s, 1H), 7.64 (dd, J=7.2, 1.6 Hz, 2 H), 7.41-7.28 (m, 4 H), 5.16 (d, J=15.2Hz, 1 H), 4.70 (m, 2 H), 4.39 (s, 1 H), 3.86 (m, 2 H), 3.59 (m, 2 H),3.37 (brs, 1 H), 2.31 (s, 3 H), 2.15 (m, 1 H), 1.82 (m, 1 H), 1.24 (brs,1 H).

Example 93-2N-(Azetidin-3-yl)-6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

The title compound was prepared in analogy to Example 93-1 in Scheme 44by using6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-oneand tert-butyl 3-aminoazetidine-1-carboxylate. MS obsd. (ESI⁺) [(M+H)⁺]410.1, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.24 (s, 1 H), 7.87 (s, 2 H),7.79 (s, 1 H), 7.62 (brs, 1 H), 7.45 (s, 1 H), 7.34 (d, J=8.4 Hz, 1 H),7.22 (brs, 1 H), 5.06-4.42 (m, 5 H), 3.85 (brs, 1 H), 3.59 (m, 5 H),2.32 (s, 3 H).

Example 94(4R)-4-{2-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethyl}-4,5-dihydro-1,3-oxazol-2-amine

tert-Butyl(4R)-4-{(2E)-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-vinyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a vial containing a mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (200 mg, 0.536 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1), tert-butyl(4R)-4-ethenyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (146 mg, 0.643mmol), triethylamine (0.5 mL) and N,N-dimethylformamide (1 mL), whichwas evacuated and filled with argon,di(tri-tert-butylphosphine)palladium(0) (13.7 mg, 0.0268 mmol) wasadded. The vial was caped and heated at 110° C. for 30 minutes undermicrowave irradiation. The reaction mixture was poured into water (30mL) and extracted with ethyl acetate (20 mL×3). The organic layers werecombined, washed with brine, dried over sodium sulfate and concentratedin vacuo. The residue was purified by flash column chromatography(eluting with 50% ethyl acetate in hexanes) to afford 180 mg of thedesired product as a white solid (yield was 60%).

(3R)-2-Amino-4-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl))-6-methyl-quinolin-4-yl]-butan-1-ol

A solution of tert-butyl(4R)-4-{(2E)-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-vinyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(180 mg, 0.32 mmol) in methanol was hydrogenated over 10% palladium oncarbon (30 mg) under atmospheric pressure for 2 hours at roomtemperature. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was dissolved in a solution ofhydrochloride in ethyl acetate (2 N, 10 mL) and the solution was stirredat room temperature for 2 hours. The reaction mixture was basified withan aqueous solution of sodium bicarbonate (2 N) to pH 8 and thenextracted with ethyl acetate (15 mL×3). The combined layers was driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby flash column chromatography (eluting with 10% methanol indichloromethane) to afford 90 mg of the desired product as a white solid(yield was 66.2%).

(4R)-4-{2-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethyl}-4,5-dihydro-1,3-oxazol-2-amine

The title compound was prepared in analogy to Example 38-1 in Scheme 45by using(3R)-2-amino-4-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl))-6-methyl-quinolin-4-yl]-butan-1-oland cyanogen bromide. MS obsd. (ESI⁺) [(M+H)⁺] 451, ¹H NMR (400 MHz,DMSO-d6) δ ppm 7.89 (m, J=4.7 Hz, 2 H), 7.72 (s, 1 H), 7.63 (t, J=3.7Hz, 1 H), 7.47 (t, J=3.9 Hz, 1 H), 7.32 (d, J=2.1 Hz, 1 H), 7.23 (d,J=2.1 Hz, 1 H), 6.85 (t, J=2.6 Hz, 1 H), 6.10 (s, 1 H), 5.15 (s, 2 H),4.53 (brs, 2 H), 3.97-3.91 (m, J=5.8 Hz, 2 H), 3.58 (t, J=2.4 Hz, 2 H),3.66-3.41 (m, J=3.3 Hz, 2 H), 2.90 (dd, J=4.2, 0.9, Hz, 1 H), 2.77 (dd,J=5.2, 0.9 Hz, 1 H), 2.42 (s, 3 H).

Example 953-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoicacid

Ethyl(2E)-3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]prop-2-enoate

A mixture of4-(4-chloro-6-ethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (300 mg, 0.78 mmol), ethyl prop-2-enoate (170 mg, 1.70mmol), triethylamine (1 mL) and N,N-dimethylformamide (2 mL),bis(tri-tert-butylphosphine)palladium(0) (15 mg, 0.02 mmol) was heatedwith stirring in a 10 mL of microwave process vial for 30 minutes at100° C. under microwave irradiation. The reaction mixture was pouredinto water (5 mL) and extracted with ethyl acetate (10 mL×3). Theorganic layers were combined, washed with brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (eluting with 20-40% ethyl acetate inpetroleum ether) to afford 280 mg of the product as a white solid (yieldwas 80%). MS obsd. (ESI⁺) [(M+H)⁺] 451.

Ethyl3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoate

To a 25 mL of dry round bottom flask containing a solution of ethyl(2E)-3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]prop-2-enoate(300 mg, 0.67 mmol) in dichloromethane (5 mL) was added2-nitrophenylsulfonylhydrazide (2.91 g, 13.4 mmol) followed by asolution of triethylamine (5 mL) in dichloromethane (10 mL) undernitrogen. The suspension was gently stirred for 6 hour at roomtemperature under nitrogen, and then concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel (eluting with20-40% ethyl acetate in petroleum ether) to afford 151 mg of the desiredproduct (yield was 50%). MS obsd. (ESI⁺) [(M+H)⁺] 453.

3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoicacid

To a solution of ethyl3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoate(100 mg, 0.22 mmol) in methanol (2 mL) was added an aqueous solution oflithium hydroxide (20.6 mg in 2 mL of water) and the resulting mixturewas stirred at room temperature for 4 hours. The reacting mixture wasacidified to pH 4 with an aqueous solution of hydrochloric acid (5 N),and then extracted with ethyl acetate (10 mL×3). The organic layers weredried over sodium sulfate and concentrated in vacuo. The residue waspurified by flash column chromatography (eluting with 1-10% methanol indichlorometane) to afford 50 mg of the product as a white solid. MS(ESI⁺) [(M+H)⁺] 425, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (brs, 2 H),7.94 (d, J=7.58 Hz, 1 H), 7.80 (brs, 1 H), 7.72 (t, J=7.07 Hz, 1 H),7.57 (d, J=7.33 Hz, 2 H), 7.37 (brs, 1 H), 5.38 (m, 2 H), 4.56 (brs, 2H), 3.94-3.69 (m, 2 H), 3.26 (brs, 2 H), 2.81-2.64 (m, 4 H), 1.22 (t,J=7.58 Hz, 3 H).

Example 963-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propan-1-amine

3-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-propionitrile

The title compound was prepared in analogy to ethyl3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoatein Example 95 in Scheme 46 by using4-(4-chloro-6-ethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and acrylonitrile.

3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propanamide

A solution of3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-propionitrile(150 mg, 0.38 mmol), and powdered potassium hydroxide (172 mg, 3.07mmol) in tert-butanol (8 mL) was heated with stirring under reflux for1.5 hours. After being cooled to room temperature, the reaction mixturewas diluted with water (15 mL) and extracted with ethyl acetate (15mL×3). The combined organic layers were dried over sodium sulfate andconcentrated in vacuo. The residue was purified by flash column (elutingwith 5% methanol in dichloromethane) to afford 125 mg of the product asa white solid.

3-[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propan-1-amine

To a solution of3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-propionamide(30 mg, 0.073 mmol) in tetrahydrofuran (2 mL) was added a solution ofborane in tetrahydrofuran (1 mL, 2 M) in an ice bath. The mixture wasstirred at 65° C. for 3 hours and then cooled naturally to roomtemperature. The reaction was quenched with methanol and the mixture wasconcentrated in vacuo. The residue was purified by preparative HPLC toafford 6.3 mg of the desired product. MS obsd. (ESI⁺) [(M+H)⁺] 396, ¹HNMR (400 MHz, CD₃OD) δ ppm 7.99 (dd, J=1.2, 8.0 Hz, 1 H), 7.88 (d, J=7.2Hz, 1 H), 7.64-7.56 (m, 3 H), 7.45 (dd, J=6.8, 7.6 Hz, 1 H), 7.37 (dd,J=1.6, 8.4 Hz, 1 H), 7.06 (s, 1 H), 5.22 (s, 2 H), 4.57 (brs, 2 H), 3.61(t, J=4.8 Hz, 2 H), 3.07 (t, J=8.0 Hz, 2 H), 2.94 (t, J=7.6 Hz, 2 H),2.45 (s, 3 H), 2.04-1.96 (m, 2 H).

Example 972-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]oxy}ethanamine

N-(2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]oxy}ethyl)acetamide

A mixture of N-(2-hydroxyethyl)-acetamide (247 mg, 2.4 mmol),4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (1000 mg, 2.4 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (190.4 mg,0.24 mmol), 1,1′-bis(diphenylphosphino)ferrocene (129.3 mg, 0.24 mmol)and sodium tert-butoxide (460.8 mg, 4.8 mmol) in 1,4-dioxane (5 mL) washeated with stirring in a sealed 10 mL of microwave process vial for 1hour at 130° C. under microwave irradiation. The reaction mixture wasconcentrated in vacuo and the residue was purified by preparative HPLCto afford 20 mg of the desired product (yield was 1.9%).

2-{[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]oxy}ethanamine

A mixture ofN-(2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]oxy}ethyl)acetamide(15 mg, 0.03 mmol) and an aqueous solution of hydrochloric acid (10 mL,37% W/W) was heated with stirring at 80° C. for 3 hours. The reactionmixture was purified by preparative HPLC and SPE to give 9.3 mg of thedesired product (yield was 68.5%). MS obsd. (ESI⁺) [(M+H)⁺] 398, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.11 (s, 1 H), 8.10-8.06 (d, J=7.6 Hz, 1 H),7.93-7.88 (d, J=7.2 Hz, 1 H), 7.82-7.76 (d, J=8 Hz, 1 H), 7.73-7.68 (t,J=7.6 Hz, 1 H), 7.65-7.60 (d, J=6.8 Hz, 1 H), 7.60-7.53 (t, J=7.2 Hz, 1H), 6.68 (s, 1 H), 5.41 (s, 2 H), 4.70-4.65 (m, 2 H), 4.65-4.45 (m, 2H), 3.80-3.72 (t, J=2.8 Hz, 2 H), 3.62-3.58 (t, J=4.4 Hz, 2 H), 2.47 (s,3 H).

Example 98-14-[6-Methyl-4-(pyrrolidin-3-yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

tert-Butyl3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]oxy}pyrrolidine-1-carboxylate

A mixture of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (134.7 mg,0.72 mmol),4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (300 mg, 0.72 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (57.12 mg,0.07 mmol), 1,1′-bis(diphenylphosphino)ferrocene (38.78 mg, 0.07 mmol)and sodium tert-butoxide (138.24 mg, 1.44 mmol) in 1,4-dioxane (5 mL)was heated with stirring in a sealed 10 mL of microwave process vial for1 hour at 130° C. under microwave irradiation. The reaction mixture wasconcentrated in vacuo and the residue was purified by preparative HPLCto afford 20 mg of the desired product (yield was 5.3%).

4-[6-Methyl-4-(pyrrolidin-3-yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

A mixture of tert-butyl3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]oxy}pyrrolidine-1-carboxylate(50 mg, 0.096 mmol) and a solution of hydrochloride in ethyl acetate (30mL, 4 M) was stirred at room temperature for 8 hours. The resultingmixture was concentrated in vacuo and the residue was purified bypreparative HPLC and SPE to afford 18.4 mg of the desired product (yieldwas 45.3%). MS obsd. (ESI⁺) [(M+H)⁺] 424, ¹H NMR (400 MHz, CD₃OD) δ ppm8.11-8.08 (d, J=6.4 Hz, 1 H), 7.95-7.88 (m, 2 H), 7.78-7.70 (m, 2 H),7.68-7.56 (m, 2 H), 6.62 (s, 1 H), 5.75-5.70 (m, 1 H), 5.40 (s, 2 H),4.70-4.50 (m, 2 H), 3.80-3.70 (m, 4 H), 3.65-3.48 (m, 2 H), 2.60-2.50(m, 1 H), 2.46 (s, 3 H), 2.46-2.35 (m, 1 H).

Example 98-28-[6-Methyl-4-(piperidin-4-yloxy)-quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

The title compound was prepared in analogy to Example 98-1 in Scheme 47by using4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) and tert-butyl4-hydroxypiperidine-1-carboxylate. MS obsd. (ESI⁺) [(M+H)⁺] 438, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.10-8.05 (d, J=8 Hz, 1 H), 7.92 (s, 1 H),7.90-7.85 (d, J=7.6 Hz, 1 H), 7.80-7.75 (d, J=8.8 Hz, 1 H), 7.75-7.68(t, J=7.6 Hz, 1 H), 7.68-7.62 (d, J=9.2 Hz, 1 H), 7.60-7.55 (t, J=7.6Hz, 1 H), 6.64 (s, 1 H), 5.38 (s, 2 H), 5.32-5.26 (m, 1 H), 4.65-4.40(m, 2 H), 3.82-3.72 (t, J=2.8 Hz, 2 H), 3.52-3.40 (m, 2 H), 3.40-3.30(m, 2 H), 2.47 (s, 3 H), 3.36-3.28 (m, 2 H), 3.20-3.10 (m, 2 H).

Example 994-(4,6-Dimethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

Diethyl (2-chloro-6-methylquinolin-4-yl)propanedioate

To a solution of 2,4-dichloro-6-methylquinoline (2.11 g, 10 mmol) and1,3-diethyl propanedioate (2.64 g, 20 mmol) in N,N-dimethylformamide (40mL) was added anhydrous potassium carbonate (2.8 g, 20 mmol). Themixture was stirred at 70° C. for 3 hours, then poured into ice/water(100 mL) and extracted with ethyl acetate (100 mL×3). The combinedorganic layers were washed with brine (150 mL×2), dried over sodiumsulfate. The residue was purified by flash column chromatography onsilica gel (eluting with 20-30% ethyl acetate in petroleum ether) toafford 1.34 g of the desired product (yield was 40%). MS obsd. (ESI⁺)[(M+H)⁺] 336.

(2-Chloro-6-methylquinolin-4-yl)acetic acid

To a solution of diethyl (2-chloro-6-methylquinolin-4-yl)propanedioate(100 mg, 0.30 mmol) in methanol (2 mL) was added an aqueous solution ofsodium hydroxide (2 N, 2 mL) and the resulting mixture was stirred atroom temperature overnight. The reaction was then acidified to pH 4 withan aqueous solution of hydrochloric acid (5 N), and extracted with ethylacetate (10 mL×3). The organic layer was dried over sodium sulfate andconcentrated in vacuo to afford the desired product as a white solid. MS(ESI⁺) [(M+H)⁺] 236.

4-(4,6-Dimethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine

A solution of (2-chloro-6-methylquinolin-4-yl)acetic acid (118 mg, 0.5mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine (247 mg, 1.5 mmol) inn-butanol (0.2 mL) was heated with stirring in a sealed 0.5 mL ofmicrowave process vial for 2 hours at 160° C. After being cooled to roomtemperature, the reaction mixture was diluted with dichloromethane (50mL), washed with a saturated aqueous solution of sodium carbonate (50mL) and brine (50 mL), dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (eluting with 20-30% ethyl acetate inpetroleum ether) to afford 100 mg of the desired product (yield was62%). MS (ESI⁺) [(M+H)⁺] 321.

4-(4,6-Dimethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

To a solution of4-(4,6-dimethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine(100 mg, 0.31 mmol) in dichloromethane (10 mL) was added3-chloroperbenzoic acid (167 mg, 70% purity, 0.78 mmol) at roomtemperature for 4 hours. The resulting mixture was washed with asaturated aqueous solution of sodium carbonate (10 mL), dried oversodium sulfate and concentrated in vacuo. The residue was purified bypreparative HPLC to afford the desired product. MS (ESI⁺) [(M+H)⁺] 353,¹H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J=7.58 Hz, 1 H), 7.88 (d,J=7.33 Hz, 1 H), 7.65 (t, J=7.20 Hz, 1 H), 7.60-7.42 (m, 3 H), 7.35 (d,J=8.34 Hz, 1 H), 7.18 (s, 1 H), 5.12 (brs, 2 H), 4.43 (brs, 2 H), 3.65(brs, 2 H), 2.53 (s, 3 H), 2.39 (s, 3 H).

Example 100[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](piperidin-4-yl)methanone

tert-Butyl4-{[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](hydroxy)methyl}piperidine-1-carboxylate

To a solution of4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine(385 mg, 1.0 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) in tetrahydrofuran (10 mL) which was cooledto −78° C., butyl lithium (0.8 mL, 1.3 mmol) was added slowly and themixture was stirred for 5 minutes, followed by the addition of asolution of tert-butyl 4-formylpiperidine-1-carboxylate (153 mg, 1.3mmol) in tetrahydrofuran (5 mL) slowly. After being stirred further at−78° C. for 2 hours, the reaction mixture was diluted with a saturatedaqueous solution of ammonium chloride (10 mL) and extracted withdichloromethane (20 mL×2). The organic layers were combined, dried oversodium sulfate and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (eluting with 20-40% ethylacetate in petroleum ether) to afford 360 mg of the desired product(yield was 70%). MS (ESI⁺) [(M+H)⁺] 520.

tert-Butyl4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](hydroxy)methyl}piperidine-1-carboxylate

To a solution of tert-butyl4-{[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](hydroxy)methyl}piperidine-1-carboxylate(519 mg, 1.0 mmol) in dichloromethane (10 mL) was added3-chloroperbenzoic acid (537 mg, 70% purity, 2.2 mmol). After beingstirred at room temperature for 4 hours, to the above mixture was addeda saturated aqueous solution of sodium thiosulfate (3 mL). The separatedorganic layer was washed with a saturated aqueous solution of sodiumcarbonate (5 mL) and brine (5 mL), dried over sodium sulfate andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (eluting with 20-50% ethyl acetate inpetroleum ether) to afford 300 mg of the desired product. MS (ESI⁺)[(M+H)⁺] 552.

tert-Butyl4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbonyl}piperidine-1-carboxylate

To a solution of tert-butyl4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](hydroxy)methyl}piperidine-1-carboxylate(200 mg, 0.36 mmol) in dichloromethane (10 mL) was added Dess-Martinreagents (226 mg, 0.54 mmol). The resulting mixture was stirred at roomtemperature until the reaction was complete monitoring by LC/MS and thenconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (eluting with 20-30% ethyl acetate inpetroleum ether) to afford 150 mg of the desired product. MS (ESI⁺)[(M+H)⁺] 550.

[2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](piperidin-4-yl)methanone

To a solution of tert-butyl4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbonyl}piperidine-1-carboxylate(100 mg, 0.18 mmol) in dichloromethane (1 mL) was added trifluoroaceticacid (1 mL). The resulting mixture was stirred at room temperature untilthe reaction was complete monitoring by LC/MS and then concentrated invacuo. The residue was purified by flash column chromatography on silicagel (eluting with 1-10% methanol in dichloromethane) to afford 60 mg ofthe desired product. MS (ESI⁺) [(M+H)⁺] 450, ¹H NMR (400 MHz, CD₃OD) δppm 8.01 (dd, J=7.83, 1.26 Hz, 1 H), 7.90 (d, J=7.07 Hz, 1 H), 7.68-7.56(m, 2 H), 7.51-7.38 (m, 3 H), 7.34 (s, 1 H), 5.26 (brs, 2 H), 4.5 (brs,2 H), 3.70-3.58 (m, 2 H), 3.37 (s, 2 H), 3.35-3.32 (m, 1 H), 3.14-3.03(m, 2 H), 2.71 (td, J=12.25, 2.78 Hz, 2 H), 2.40 (s, 3 H), 1.79 (m, 2H), 1.69-1.51 (m, 2 H).

Example 1014-[6-Methyl-4-(1H-pyrazol-3-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

To a solution of8-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (115 mg, 0.28 mmol, prepared in analogy to4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide in Example 17-1) in dimethoxyethane (8 mL) was added(triphenylphosphine) palladium (20 mg). After the mixture was stirredfor 10 minutes, 1H-pyrazole-3-boric acid (107 mg, 0.84 mmol) was addedfollowed by an aqueous solution of sodium carbonate (1 M, 0.5 mL). Theresulting mixture was sealed and heated with stirring in a sealed 10 mLof microwave process vial for 1 hour at 80° C. under microwaveirradiation. The reaction mixture was then purified by preparative HPLCto afford 36.5 mg of the desired product (yield was 10.8%). MS (ESI⁺)[(M+H)⁺] 405, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.41 (s, 1 H), 8.09-8.02 (m,2 H), 7.95 (s, 2 H), 7.69-7.53 (m, 4 H), 6.99 (s, 1 H), 5.48 (s, 2 H),4.67 (s, 2 H), 3.81 (s, 2 H), 3.34 (s, 1 H), 2.44 (s, 3 H).

Example 1024-[6-Methyl-4-(phenylsulfonyl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

4-[6-Methyl-4-(phenylsulfanyl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

A mixture of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (1.8 g, 5.0 mmol, prepared in analogy to the one in Example17-1), benzenethiol (0.66 g, 6.0 mmol) and N,N-dimethylpyridin-4-amine(0.74 g, 6 mmol) in dry ethanol (40 mL) was stirred at room temperaturefor 3 days. The reaction mixture was filtered and concentrated in vacuo.The residue was purified by silica gel column (gradient eluting with10-20% ethyl acetate in hexanes) to afford 1.0 g of the desired product(yield was 45%).

4-[6-Methyl-4-(phenylsulfonyl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide

A mixture solution of4-[6-methyl-4-(phenylsulfanyl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (223 mg, 0.5 mmol) and 3-chloroperbenzoic acid (340 mg, 2mmol) in dry dichloromethane (30 mL) was stirred at 0° C. for 2 hours.After the reaction was quenched with a saturated aqueous solution ofsodium thiosulphate (15 mL), the resulting mixture was stirred furtherat room temperature for 15 minutes. The separated organic layer waswashed with a saturated aqueous solution of sodium bicarbonate (15 mL)and a saturated aqueous solution of sodium thiosulphate (15 mL), driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby preparative HPLC to afford 168 mg of the desired product (yield was70%). MS (ESI⁺) [(M+H)⁺] 479, ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11-8.08(dd, J=1.2, 8 Hz, 1 H), 8.05 (s, 1 H), 7.91-7.89 (t, J=3.6 Hz, 3 H),7.75-7.38 (d, J=6.8 Hz, 1 H), 7.65-7.58 (m, 3 H), 7.53-7.45 (m, 3 H),7.41-7.39 (dd, J=1.6, 8.4 Hz, 1 H), 5.25 (s, 2 H), 5.15-4.20 (brs, 2 H),3.58 (s, 2 H), 2.42 (s, 3 H).

Example 103N-(2-Aminoethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinoline-4-sulfonamide

2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinoline-4-thiol

To a solution of4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide (1.5 g, 4 mmol, prepared in analogy to the one in Example17-1) in dry N,N-dimethylformamide (100 mL) was added sodiummethanethiolate (1.4 g, 20 mmol) under argon protection. The reactionwas stirred at 130° C. for 16 hours. The reaction mixture was cooled to50° C. and concentrated in vacuo. The residue was dissolved in cooledwater (150 mL) and carefully acidified with 20% of hydrochloric acid topH 4˜5 under argon atmosphere. The resultant solution was extracted withcooled dichloromethane (150 mL×3). The combined organic layer was washedwith cooled brine (100 mL×2) and concentrated in vacuo at roomtemperature to afford the crude product, which was used for next stepwithout further purification.

2-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinoline-4-sulfonylchloride

Gaseous chlorine was passed through a well stirred solution of2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinoline-4-thiol(the crude product from the above step) in concentrated hydrochloricacid (10 mL) at −10° C. at such a rate that temperature was maintainedbetween −5° C.˜−10° C. After been stirred for 30 minutes, the passage ofchlorine was discontinued and the mixture was poured onto ice (10 g)followed by the addition of sodium bicarbonate (8 g) in small portions.The resulting mixture was extracted with cooled dichloromethane (100mL×3). The combined organic layer was washed with cooled water (100 mL),dried over sodium sulfate and filtered. The filtrate was used for thenext step without further purification.

N-(2-Aminoethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinoline-4-sulfonamide

To a cooled solution of ethane-1,2-diamine (320 mg, 5.4 mmol) indichloromethane (50 mL) was added triethylamine (3 drops) followed by2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinoline-4-sulfonylchloride (the filtrate from the above step) at 0° C. The resultingmixture was stirred at room temperature for 16 hours and concentrated invacuo. The residue was purified by preparative HPLC to afford 56.38 mgof the desired product (yield of three steps was 3.1%). MS (ESI⁺)[(M+H)⁺] 461, ¹H NMR (400 MHz, CD₃OD) δ ppm 8.11 (s, 1 H), 7.99-7.97 (d,J=8.4 Hz, 1 H), 7.85-7.83 (d, J=7.6 Hz, 1 H), 7.67-7.63 (m, 3 H),7.49-7.45 (m, 2 H), 5.25 (s, 2 H), 4.76-4.03 (m, 2 H), 3.63-3.59 (t, 2H), 3.03-3.00 (m, 4 H), 2.46 (s, 3 H).

Example 104 Methyl4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate

Methyl4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate

To a stirred solution of methyl4-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate(1.5 g, 3.9 mmol) in dichloromethane (20 ml) was added3-chloroperbenzoic acid (1.68 g, 9.7 mmol) at 0° C. The reaction mixturewas stirred at 0° C. for 20 minutes and the reaction was quenched with asaturated aqueous solution of sodium carbonate (10 mL). The separatedorganic layer was washed with a saturated aqueous solution of sodiumcarbonate (10 mL) and brine (10 mL), dried over sodium sulfate andconcentrated in vacuo. The residue was purified by flash columnchromatography (eluting with 5% methanol in dichloromethane) to afford1.38 g of the desired product as a white solid (yield was 85%).

Methyl4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate

The title compound was prepared in analogy to Example 6-1 in Scheme 52by using methyl4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylateand oxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 497, ¹H NMR(400 MHz, DMSO-d6) δ ppm 8.57 (d, 1 H), 7.95 (d, 1 H), 7.85 (m, 2 H),7.71 (t, 1 H), 7.61 (m, 1 H), 7.46-7.38 (m, 2 H), 6.18 (s, 1 H), 5.07(s, 2 H), 4.32 (m, 6 H), 3.80 (s, 3 H), 3.55 (m, 4 H), 2.95 (s, 2 H).

Example 1054-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylicacid

To a stirred solution of methyl4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate(100 mg, 0.2 mmol) in tetrahydrofuran and water (4 mL, V/V=3/1) wasadded sodium hydroxide (40 mg, 1.0 mmol). After being stirred at roomtemperature overnight, the resulting mixture was concentrated in vacuoto remove the organic solvent. The residual aqueous solution wasacidified with an aqueous solution of citric acid (5 mL, 20%) andextracted with dichloromethane (15 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate and concentrated in vacuo toafford a sticky solid, which was purified by flash column chromatography(eluting with 5% methanol in dichloromethane) to afford 20 mg of thedesire product as a solid. MS obsd. (ESI⁺) [(M+H)⁺] 483, ¹H NMR (400MHz, DMSO-d6) δ ppm 8.78 (s, 1 H), 8.01 (d, 1 H), 7.90 (m, 2 H), 7.61(t, 1 H), 7.47 (t, 1 H), 7.32 (d, 1 H), 6.29 (s, 1 H), 5.76 (s, 2 H),4.40 (m, 6 H), 3.78 (s, 2 H), 3.62 (s, 2 H), 3.17 (m, 2 H).

Example 106[4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol

[4-Chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol

To a slurry of lithium aluminum hydride (46 mg, 1.21 mmol) intetrahydrofuran (5 mL) was added a solution of methyl4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate(400 mg, 0.96 mmol) in tetrahydrofuran (10 mL) at 0° C. under a nitrogenatmosphere. After being allowed to warm to room temperature and stirredfor 2 hours, the reaction mixture was cooled to 0° C. and treated withwater (0.2 mL) to quench the reaction. The resulting mixture was stirredfor 30 minutes, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to afford 321 mg of the desired product as a whitesolid (yield was 86%).

[4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol

The title compound was prepared in analogy to Example 6-1 in Scheme 52by using[4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanoland oxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 469, ¹H NMR(400 MHz, DMSO-d6) δ ppm 7.93 (d, 1 H), 7.83 (m, 1 H), 7.75 (s, 1 H),7.59 (m, 1 H), 7.42 (m, 1 H), 7.34 (s, 2 H), 7.25 (t, 1 H), 6.13 (s, 1H), 5.10 (t, 1 H), 5.04 (s, 2 H), 4.47 (d, 2 H), 4.34 (m, 6 H), 3.58 (d,2 H), 3.52 (d, 2 H), 2.96 (t, 2 H), 1.79 (m, 2 H).

Example 107N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-6-trideuteriomethyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

4-(Benzyloxy)-6-bromo-2-chloroquinazoline

To a cooled solution of 6-bromo-2,4-dichloroquinazoline (1.39 g, 5 mmol)in tetrahydrofuran (50 mL) was added a solution of benzyl alcohol (0.52mL, 5 mmol) and sodium hydride (210 mg, 5.25 mmol, 60% in mineral oil)in tetrahydrofuran (15 mL) dropwise at 0° C. After being stirred at roomtemperature for 2 hours, the reaction mixture was poured into cold water(10 mL) and then extracted with ethyl acetate (50 mL). The organic layerwas dried over magnesium sulfate and concentrated in vacuo to afford1.73 g of the desired product as a yellow solid (yield was 99%).

4-[4-(Benzyloxy)-6-bromoquinazolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine

A mixture of 4-(benzyloxy)-6-bromo-2-chloroquinazoline (700 mg, 2.0mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine (990 mg, 6.0 mmol) washeated at 80° C. for 10 minutes. The resulting reaction mixture wascooled to room temperature and purified by silica gel columnchromatography (eluting with dichloromethane) to afford 600 mg of thedesired product as a white solid (yield was 62.7%).

4-[4-(Benzyloxy)-6-trideuteriomethylquinazolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine

To a cooled solution of4-[4-(benzyloxy)-6-bromoquinazolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine(239 mg, 0.50 mmol) in anhydrous tetrahydrofuran (10 mL) was addedn-butyllithium (0.5 mL, 0.80 mmol) in tetrahydrofuran dropwise over 5minutes under a nitrogen atmosphere at −78° C., followed by addition ofmethyl-d³ trifluoromethanesulfonate (134 mg, 0.80 mmol) dropwise at −78°C. over 5 minutes. After being stirred for 1 hour at −78° C., thereaction mixture was allowed to warm to room temperature and stirred foranother 1 hour. The reaction was quenched with deuterated water (5 mL).The resulting mixture was extracted with ethyl acetate (20 mL). Theorganic layer was dried over sodium sulfate and concentrated in vacuo toafford the desired compound.

4-[4-(Benzyloxy)-6-trideuteriomethylquinazolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide

To a solution of4-[4-(benzyloxy)-6-trideuteriomethylquinazolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine(417 mg, 1.0 mmol) in dichloromethane (10 mL) was added3-chloroperoxybenzoic acid (233 mg, 1.0 mmol, 75%). After being stirredfor 1 hour, the mixture was washed with a saturated aqueous solution ofsodium thiosulphate (3 mL), 10% aqueous solution of sodium hydroxide (5mL) and brine (5 mL). The organic layer was dried over sodium sulfateand concentrated in vacuo. The residue was purified by silica gel columnchromatography (eluting with 10% ethyl acetate in dichloromethane) toafford the desired product as a white solid.

N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-trideuteriomethyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine

A mixture of4-[4-(benzyloxy)-6-trideuteriomethylquinazolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide (700 mg, 1.62 mmol) and oxetane-3,3-diyldimethanamine (752 mg,6.5 mmol) was heated at 170° C. for 20 minutes, then the mixture wascooled to room temperature and then purified by preparative HPLC toafford 60 mg of the desired product as a white solid (yield was 8.4%).MS obsd. (ESI⁺) [(M+H)⁺] 441, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.78-7.73(m, 2 H), 7.69-7.67 (m, 1 H), 7.62-7.45 (m, 2 H), 7.44-7.40 (m, 1 H),7.38-7.34 (m, 1 H), 5.27 (d, J=16 Hz, 1 H), 4.77 (brs, 1 H), 4.68-4.64(m, 2 H), 4.52-4.47 (m, 2 H), 4.11-4.01 (m, 2 H), 3.49-3.35 (m, 2 H),3.50-3.40 (m, 1 H), 3.40-3.34 (m, 1 H), 3.04 (s, 2 H).

Example 108-14-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylicacid

Methyl4-(benzyloxy)-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylate

To a solution of4-(4-benzyloxy-6-bromoquinazolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine(239 mg, 0.5 mmol) in anhydrous tetrahydrofuran (10 mL) was addedn-butyllithium (0.5 mL, 0.8 mmol) in tetrahydrofuran dropwise at −78° C.under nitrogen atmosphere over 5 minutes followed by addition of dry ice(2.5 mmol) at −78° C. After being stirred for 1 hour at −78° C., thereaction mixture was allowed to warm to room temperature and stirred foranother 1 hour. The reaction was quenched by addition of a saturatedsolution of ammonium chloride (10 mL) and extracted with ethyl acetate(25 mL). The organic layer was dried over sodium sulfate andconcentrated in vacuo to afford the crude product of the acid. To asolution of the above crude acid in methanol (15 mL) was added sulfinylchloride (2 mL) at 0° C., then the mixture was heat at 70° C. for 1hour. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was dissolved in ethyl acetate, andthe solution was washed with a saturated aqueous solution of sodiumbicarbonate, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by flash column chromatography (eluting with 10%ethyl acetate in dichloromethane) to afford the desired methyl ester.

Methyl4-(benzyloxy)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylateand Methyl 4-(benzyloxy)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin4(5H)-yl)quinazoline-6-carboxylate

To a solution of methyl4-(benzyloxy)-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylate(800 mg, 1.75 mmol) in dichloromethane was added m-chloroperoxybenzoicacid (602 mg, 2.625 mmol, 75% purity) slowly, then the mixture wasstirred at room temperature for 1 hour. The reaction mixture was washedwith a saturated aqueous solution of sodium thiosulphate, and 10%aqueous solution of sodium hydroxide, and brine. The resulting organiclayer was dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by flash column chromatography (eluting with 10%ethyl acetate in dichloromethane) to afford 350 mg of methyl4-(benzyloxy)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylateand 400 mg of methyl4-(benzyloxy)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylate.

4-(Benzyloxy)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylicacid

To the solution of methyl4-(benzyloxy)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylate(350 mg, 0.74 mmol) in the mixture of tetrahydrofuran and water (10 mL,V/V=4:1) was added lithium hydroxide (178 mg, 7.4 mmol). The resultingmixture was stirred at room temperature overnight and then acidifiedwith hydrochloric acid (2 N), extracted with ethyl acetate. The organiclayer was dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by flash column chromatography (eluting with 10%ethyl acetate in dichloromethane) to afford4-(benzyloxy)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylicMS obsd. (ESI⁺) [(M+H)⁺] 460.

4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylicacid

A mixture of 4-(benzyloxy)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylic acid (170 mg, 0.37 mmol) andoxetane-3,3-diyldimethanamine (128 mg, 1.11 mmol) was heated at 170° C.for 30 minutes. Then the reaction mixture was cooled to room temperatureand purified by preparative HPLC to afford4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylicacid, MS obsd. (ESI⁺) [(M+H)⁺] 468, ¹H NMR (400 MHz, DMSO-d6) δ ppm8.91-8.61 (m, 2 H), 8.09-8.00 (m, 1 H), 7.77-7.74 (m, 1 H), 7.68-7.65(m, 1 H), 7.51-7.42 (m, 2 H), 7.27-7.13 (m, 1 H), 5.26-5.17 (m, 2 H),4.89-4.68 (m, 4 H), 452-4.45 (m, 2 H), 4.40-4.31 (m, 2 H), 4.10-3.84 (m,2 H), 3.20-3.01 (m, 2 H).

Example 108-24-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylicacid

The title compound was prepared in analogy to Example 108-1 in Scheme 54by using4-(benzyloxy)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylicacid and oxetane-3,3-diyldimethanamine, MS obsd. (ESI⁺) [(M+H)⁺] 484, ¹HNMR (400 MHz, DMSO-d6) δ ppm 8.95 (brs, 1 H), 8.68 (m, 1 H), 8.04 (d,J=9.1 Hz, 1 H), 7.77-7.73 (m, 2 H), 7.68-7.63 (m, 1 H), 7.48-7.43 (m, 1H), 7.24-7.19 (m, 1 H), 5.11 (brs, 2 H), 4.59-4.30 (brs, 6 H), 4.20 (m,1 H), 4.0 (m, 1 H), 3.58 (brs, 2 H), 3.12 (m, 2 H).

Example 109-1 and Example 109-2[4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanoland[4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol

4-(Benzyloxy)-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carbaldehyde

To a cooled solution of4-(4-benzyloxy-6-bromoquinazolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine(500 mg, 1.048 mmol) in anhydrous tetrahydrofuran (10 mL) was addedanhydrous N,N-dimethylformamide (150 μL, 1.94 mmol) at −78° C. Afterbeing stirred at −78° C. for 30 minutes, the mixture was warmed to roomtemperature, diluted with water (10 mL) and extracted with ethyl acetate(20 mL×3). The combined organic layers were washed with a saturatedaqueous solution of ammonium chloride (40 mL) and brine (40 mL), driedover anhydrous sodium sulfate, and concentrated in vacuo to afford 410mg of the crude product as a yellow solid. MS obsd. (ESI⁺) [(M+H)⁺] 428.

[4-(Benzyloxy)-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol

To a solution of4-(benzyloxy)-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carbaldehyde(3.0 g, 7.0 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) wasadded sodium borohydride (270 mg, 7.13 mmol) at 0° C. After beingstirred at 0° C. for 15 minutes, the resulting mixture was warmed toroom temperature, diluted with water (10 mL) and extracted with ethylacetate (20 mL×3). The combined organic layers were washed with asaturated aqueous solution of ammonium chloride (40 mL) and brine (40mL), dried over anhydrous sodium sulfate, and concentrated in vacuo toafford 2.85 g of the desired product as a yellow solid (yield was 95%),MS obsd. (ESI⁺) [(M+H)⁺] 430.

[4-(Benzyloxy)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanoland[4-(Benzyloxy)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol

To a solution of[4-(benzyloxy)-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol(1.0 g, 2.33 mmol) in dichloromethane (20 mL) was added3-chloroperoxybenzoic acid (536 mg, 2.33 mmol, 75% purity) at 0° C.After being stirred at 0° C. for 15 minutes, the mixture was warmed toroom temperature, diluted with water, extracted with dichloromethane (20mL×3). The combined organic layers were washed with a saturated aqueoussolution of sodium bicarbonate (40 mL) and brine (40 mL), dried overanhydrous sodium sulfate, and concentrated in vacuo to afford 0.90 g ofthe mixture of[4-(benzyloxy)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanoland[4-(benzyloxy)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanolas a yellow solid.

[4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanoland[4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol

A mixture of[4-(benzyloxy)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanoland[4-(benzyloxy)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol(700 mg, about 1.57 mmol) and oxetane-3,3-diyldimethanamine (700 mg,6.03 mmol) was heated at 160° C. for 30 minutes. After being cooled toroom temperature, the reaction mixture was diluted with water (10 mL),extracted with dichloromethane (20 mL×3). The organic layers were washedwith brine (40 mL), dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by preparative HPLC to afford[4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol,MS obsd. (ESI⁺) [(M+H)⁺] 454, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.139 (s,1 H), 7.918 (s, 1 H), 7.71 (m, 2 H), 7.48 (m, 3 H), 7.316 (d, J=8 Hz, 1H), 5.21 (m, 2 H), 4.75 (m, 2 H), 4.51 (m, 4 H), 4.369 (s, 3 H), 3.93(brs, 1 H), 3.15 (brs, 2 H), 2.989 (s, 2 H), and[4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol,MS obsd. (ESI⁺) [(M+H)⁺] 470, ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.197 (s,1 H), 7.789 (m, 3 H), 7.62 (t, J=7.2 Hz, 1 H), 7.48 (m, 2 H), 7.316 (s,1 H), 5.12 (m, 3 H), 4.48 (m, 8 H), 3.917 (s, 2 H), 3.569 (brs, 2 H),2.951 (brs, 2 H).

Example 110-1N-[(3-Aminooxetan-3-yl)methyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine

2-(4-Chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzo[c]azepine

A solution of 2,4-dichloro-6-methylquinoline (500 mg, 2.358 mmol) and5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine (432 mg, 2.358 mmol) inn-butanol (10 mL) was heated at 160° C. for 5 hours under microwaveirradiation. The resulting reaction mixture was poured into water (10mL) and extracted with ethyl acetate (20 mL×3). The combined organiclayers were dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by flash column chromatography (eluting with 20%ethyl acetate in petroleum ether) to afford 550 mg of the desiredproduct as a solid (yield was 65%).

N-[(3-Aminooxetan-3-yl)methyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine

A solution of2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine(250 mg, 0.697 mmol), 3-(aminomethyl)oxetan-3-amine (119 mg, 0.697 mmol,purity: 60%), 1,1′-bis(diphenylphosphino)ferrocene (39 mg, 0.0697 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (51 mg,0.0697 mmol), sodium tert-butoxide (134 mg, 1.394 mmol). in 1,4-dioxane(10 mL) was heated at 120° C. for 1.5 hours under microwave irradiation.The resulting reaction mixture was poured into water (10 mL) andextracted with dichloromethane (20 mL×3), the combined organic layerswere dried over sodium sulfate and concentrated in vacuo. The residuewas purified by flash column chromatography (eluting with 0-10% methanolin dichloromethane) and preparative HPLC to afford 14 mg of the productas a white solid (yield was 4.4%). MS obsd. (ESI⁺) [(M+H)⁺] 425, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.67-7.65 (d, J=6.8 Hz, 2 H), 7.61-7.59 (d, J=7.6Hz, 1 H), 7.46-7.39 (m, 2 H), 7.33-7.29 (m, 2 H), 6.15 (s, 1 H), 4.91(s, 2 H), 4.63-4.61 (d, J=6.4 Hz, 2 H), 4.58-4.56 (d, J=6.4 Hz, 2 H),4.32-4.29 (t, J=5.5, 5.6 Hz, 2 H), 3.64 (s, 2 H), 2.55-2.45 (m, 2 H),2.42 (s, 3 H).

Example 110-2N-[2-(2-Aminoethoxy)ethyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand 2-(2-aminoethoxy)ethan-1-amine. MS obsd. (EST) [(M+H)⁺] 427, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.60-7.50 (d, J=7.2 Hz 1 H), 7.50-7.40 (d, J=9.2Hz, 1 H), 7.40-7.30 (d, J=7.6 Hz, 1 H), 7.30-7.15 (m, 5 H), 5.85 (s, 1H), 5.05 (s, 1 H), 4.75 (s, 2 H), 4.30 (s, 2 H), 3.75-3.65 (m, 2 H),3.55-3.45 (m, 2 H), 3.40-3.30 (m, 2 H), 2.90-2.80 (t, 2 H), 2.50-2.40(m, 2 H), 2.35 (s, 3 H).

Example 110-3N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-N′-methylethane-1,2-diamine

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand (2-aminoethyl)(methyl)amine. MS obsd. (ESI⁺) [(M+H)⁺] 397, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.60-7.50 (d, J=7.2 Hz, 1 H), 7.45-7.30 (m, 2 H),7.30-7.10 (m, 5 H), 5.85 (s, 1 H), 5.25 (s, 1 H), 4.80 (s, 2 H), 4.30(s, 2 H), 3.35-3.20 (m, 2 H), 2.97-2.85 (m, 2 H), 2.50-2.40 (m, 5 H),2.35 (s, 3 H).

Example 110-41-Amino-3-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}propan-2-ol

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand 1,3-diaminopropan-2-ol. MS obsd. (ESI⁺) [(M+H)⁺] 413, ¹H NMR (400MHz, CD₃OD) δ ppm 7.60-7.50 (d, J=7.6 Hz, 1 H), 7.45-7.35 (m, 2 H),7.30-7.10 (m, 5 H), 5.85 (s, 1 H), 5.20 (s, 1 H), 4.78 (s, 2 H), 4.30(s, 2 H), 3.85-3.75 (m, 1 H), 3.35-3.20 (m, 1 H), 3.20-3.10 (m, 1 H),3.00-2.90 (m, 1 H), 2.75-2.65 (m, 1 H), 2.45-2.35 (m, 2 H), 2.32 (s, 3H).

Example 110-53-{[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand 3-aminopropane-1,2-diol. MS obsd. (ESI⁺) [(M+H)⁺] 414, ¹H NMR (400MHz, CDCl₃) δ ppm 7.60-7.50 (d, J=7.6 Hz, 1 H), 7.50-7.40 (d, J=8.4 Hz,2 H), 7.35-7.25 (d, J=8.4 Hz, 2 H), 7.25-7.10 (m, 2 H) 5.85 (s, 1 H),5.20 (s, 1 H), 4.78 (s, 2 H), 4.20 (s, 2 H), 3.95-3.85 (m, 1 H),3.70-3.50 (m, 2 H), 3.20-3.10 (m, 2 H), 2.50-2.40 (m, 2 H), 2.32 (s, 3H).

Example 110-63-{[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}propan-1-ol

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand 3-aminopropane-1-ol. MS obsd. (ESI⁺) [(M+H)⁺] 398, ¹H NMR (400 MHz,CD₃Cl) δ ppm 7.60-7.40 (m, 3 H), 7.35-7.25 (m, 4 H), 5.85 (s, 1 H), 4.80(s, 2 H), 4.30 (s, 2 H), 3.90-3.80 (m, 2 H), 3.45-3.30 (m, 2 H),2.55-2.45 (m, 2 H), 2.38 (s, 3 H).

Example 110-72-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methyl-N-[2-(piperazin-1-yl)ethyl]quinolin-4-amine

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand 2-(piperazin-1-yl)ethan-1-amine. MS obsd. (ESI⁺) [(M+H)⁺] 452, ¹HNMR (400 MHz, CD₃Cl) δ ppm 7.52-7.44 (d, J=8.8 Hz, 1 H), 7.41-7.40 (m, 2H), 7.25-7.10 (m, 4 H), 5.80 (s, 1 H), 5.51 (s, 1 H), 4.79 (s, 2 H),4.26 (s, 2 H), 3.21-3.17 (m, 2 H), 2.86-2.84 (m, 4 H), 2.70-2.67 (m, 2H), 2.44-2.42 (m, 6 H), 2.35 (s, 3 H).

Example 110-8N^(˜)1^(˜)-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]propane-1,2-diamine

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand propane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 397, ¹H NMR (400 MHz,CD₃Cl) δ ppm 7.54-7.52 (d, J=7.6 Hz, 1 H), 7.47-7.45 (d, J=8.4 Hz, 1 H),7.40-7.38 (d, J=7.6 Hz, 1 H), 7.25-7.16 (m, 4 H) 5.85 (s, 1 H), 5.25 (s,1 H), 4.78 (s, 2 H), 4.29-4.24 (m, 2 H), 3.22-3.17 (m, 2 H), 2.91-2.89(m, 1 H), 2.46-2.33 (m, 2 H), 2.32 (s, 3 H), 1.20-1.18 (m, 3 H).

Example 110-9cis-N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]cyclohexane-1,4-diamine

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand cis-cyclohexane-1,4-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.60-7.50 (d, J=7.6 Hz, 1 H), 7.50-7.40 (d, J=8.4Hz, 1 H), 7.40-7.30 (d, J=7.6 Hz, 1 H), 7.30-7.15 (m, 5 H), 5.95 (s, 1H), 4.80-4.70 (d, J=4.0 Hz, 2 H), 4.60 (s, 2 H), 4.05 (s, 1 H), 3.10 (s,1 H), 2.70-2.60 (m, 1 H), 2.50-2.40 (m, 2 H), 2.35 (s, 3 H), 2.05 (s, 2H), 1.80 (s, 2 H), 1.50-1.30 (m, 4 H).

Example 110-102-(9,9-Difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand pyrrolidin-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 409, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.60-7.50 (d, J=7.6 Hz, 1 H), 7.50-7.40 (d, J=8.8 Hz, 1 H),7.40-7.30 (d, J=7.2 Hz, 1 H), 7.30-7.20 (m, 4 H), 5.85 (s, 1 H), 4.75(s, 2 H), 4.30 (s, 2 H), 4.05 (s, 1 H), 3.65 (s, 1 H), 3.30-3.20 (m, 1H), 3.20-2.90 (m, 3 H), 2.50-2.40 (m, 2 H), 2.35 (s, 3 H), 2.20-2.10 (m,2 H).

Example 110-112,2′-{[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]imino}diethanol

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand 2,2′-iminodiethanol. MS obsd. (ESI⁺) [(M+H)⁺] 428, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.90-7.70 (m, 2 H), 7.70-7.60 (m, 2 H), 7.50-7.30 (m, 3 H),6.40 (s, 1 H), 5.85 (s, 2 H), 4.65 (s, 2 H), 4.15 (s, 2 H), 3.85 (s, 3H), 3.58 (s, 2 H), 3.25 (s, 2 H), 2.60-2.50 (m, 3 H), 2.35 (s, 3 H).

Example 110-12N˜1˜-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-2-methylpropane-1,2-diamine

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand 2-methylpropane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR(400 MHz, CD₃OD) δ ppm 8.06 (s, 1 H), 7.79-7.69 (m, 3 H), 7.61-7.58 (dd,J=8.8, 1.6 Hz, 1 H), 7.53-7.49 (t, J=7.6 Hz, 1 H), 7.46-7.42 (t, J=7.6Hz, 1 H), 6.13 (s, 1 H), 5.12 (s, 2 H), 4.24-4.21 (t, J=5.6 Hz, 2 H),3.76 (s, 2 H), 2.73-2.64 (m, 2 H), 2.48 (s, 3 H), 1.42 (s, 6 H).

Example 110-135,5-Difluoro-2-[6-methyl-4-(4-methylpiperazin-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand 1-methylpiperazine. MS obsd. (ESI⁺) [(M+H)⁺] 423, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.93-7.91 (d, J=8.4 Hz, 1 H), 7.77-7.75 (d, J=7.6 Hz, 1 H),7.71-7.69 (d, J=7.6 Hz, 1 H), 7.69 (s, 1 H), 7.62-7.60 (d, J=7.6 Hz, 1H), 7.56-7.52 (t, J=8 Hz, 1 H), 7.49-7.45 (t, J=8 Hz, 1 H), 6.58 (s, 1H), 5.18 (s, 2 H), 4.32-4.29 (t, J=6 Hz, 2 H), 3.97-3.89 (m, 2 H),3.77-3.68 (m, 2H), 3.61-3.51 (m, 2 H), 3.50-3.39 (m, 2 H), 3.03 (s, 3H), 2.79-2.67 (m, 2 H), 2.49 (s, 3 H).

Example 110-141-[2-(9,9-Difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)-6-methylquinolin-4-yl]-3-ethylurea

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand ethylurea. MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz, CDCl₃) δppm 12.30 (s, 1 H), 9.62-9.55 (m, 1 H), 8.40-8.20 (m, 1 H), 7.82-7.70(m, 2 H), 7.60-7.38 (m, 4 H), 7.12 (s, 1 H), 5.00-4.80 (m, 2 H),4.50-4.10 (m, 2 H), 3.42-3.30 (m, 2 H), 2.70-2.50 (m, 2 H), 1.92 (s, 3H), 1.31-1.20 (t, J=7.2 Hz, 3 H).

Example 110-15N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 110-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand oxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 439, ¹H NMR(400 MHz, CDCl₃) δ ppm 8.08 (s, 1 H), 7.80 (m, 3 H), 7.67 (d, 1 H), 7.60(t, 1 H), 7.54 (t, 1 H), 6.18 (s, 1 H), 5.16 (s, 2 H), 4.68-4.62 (m, 4H), 4.32 (t, 2 H), 3.94 (s, 2 H), 3.54 (s, 2 H), 2.78 (m, 2 H), 2.54 (s,3 H).

Example 111-15,5-Difluoro-2-[6-methyl-4-(piperazin-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine

A mixture of2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine(100 mg, 0.279 mmol) and piperazine (300 mg, 3.488 mmol) was heated at150° C. for 2 hours under microwave irradiation. The resulting reactionmixture was purified by preparative HPLC followed by SPE. The eluent wasconcentrated in vacuo and the residue was dried by lyophilization toafford 38.87 mg of the desired product (yield was 34.1%). MS obsd.(ESI⁺) [(M+H)⁺] 409, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.65-7.58 (d, J=7.6Hz, 1 H), 7.55-7.45 (t, 2 H), 7.40-7.30 (d, J=7.6 Hz, 1 H), 7.38-7.25(m, 2 H), 7.28-7.20 (m, 1 H), 6.35 (s, 1 H), 4.75 (s, 2 H), 4.34 (s, 2H), 3.20-3.00 (m, 8 H), 2.60-2.45 (m, 2 H), 2.43 (s, 3 H).

Example 111-22-[4-(1,4-Diazepan-1-yl)-6-methylquinolin-2-yl]-5,5-difluoro-2,3,4,5-tetrahydro-1H-2-benzazepine

The title compound was prepared in analogy to Example 111-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand [1,4]diazepane. MS obsd. (ESI⁺) [(M+H)⁺] 423, ¹H NMR (400 MHz,CD₃Cl) δ ppm 7.60-7.58 (d, J=6.8 Hz, 1 H), 7.55-7.53 (m, 2 H), 7.45-7.43(d, J=7.2 Hz, 1 H), 7.34-7.24 (m, 3 H), 6.41 (s, 1 H), 4.85 (s, 2 H),4.33-4.32 (d, J=5.2 Hz, 2 H), 3.43-3.40 (m, 4 H), 3.17-3.14 (m, 4 H),2.51-2.47 (m, 2 H), 2.41 (s, 3 H), 2.20 (brs, 1 H), 2.04-2.01 (m, 2 H).

Example 111-3N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-N-methylethane-1,2-diamine

The title compound was prepared in analogy to Example 111-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand (2-aminoethyl)(methyl)amine. MS obsd. (ESI⁺) [(M+H)⁺] 397, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.60-7.50 (d, J=7.2 Hz, 1 H), 7.45-7.35 (m, 2 H),7.30-7.10 (m, 5 H), 5.85 (s, 1 H), 5.25 (s, 1 H), 4.78 (s, 2 H), 4.30(s, 2 H), 3.35-3.20 (m, 2 H), 2.97-2.80 (m, 2 H), 2.50-2.35 (m, 5 H),2.40-2.30 (s, 3 H).

Example 111-41-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine

The title compound was prepared in analogy to Example 111-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand pyrrolidin-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 409, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.65 (s, 1 H), 7.62-7.55 (d, J=7.6 Hz, 1 H), 7.55-7.45 (d,J=8.8 Hz, 1 H), 7.45-7.40 (d, J=7.2 Hz, 1 H), 7.40-7.30 (t, 1 H),7.30-7.20 (m, 3 H), 5.85 (s, 1 H), 4.85 (s, 2 H), 4.30 (s, 2 H),3.80-3.70 (m, 3 H), 3.60-3.50 (m, 2 H), 3.40-3.30 (m, 1 H), 2.50-2.40(m, 2 H), 2.35 (s, 3 H), 2.30-2.10 (m, 1 H).

Example 111-52-{[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}ethanol

The title compound was prepared in analogy to Example 111-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand 2-aminoethanol. MS obsd. (ESI⁺) [(M+H)⁺] 384, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.60-7.40 (m, 3 H), 7.35-7.20 (m, 4 H), 5.87 (s, 1 H),4.88-4.87 (d, J=16.4 Hz, 2 H), 4.33 (s, 2 H), 3.90-3.87 (m, 2 H),3.41-3.37 (m, 2 H), 2.52-2.47 (m, 2 H), 2.38 (s, 3 H), 2.00-1.97 (m, 2H).

Example 111-6N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 111-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand ethane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 383, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.89 (s, 1 H), 7.72-7.70 (d, J=6.8 Hz, 1 H), 7.70-7.67 (d,J=6.8 Hz, 2 H), 7.65-7.42 (m, 3 H), 6.00 (s, 1 H), 5.02 (s, 2 H),4.23-4.20 (t, 2 H), 3.88-3.78 (t, 2 H), 3.58-3.55 (t, 2 H), 2.71-2.61(m, 2 H), 2.46 (s, 3 H).

Example 111-7N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]cyclohexane-1,3-diamine

The title compound was prepared in analogy to Example 111-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand cyclohexane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 437, ¹H NMR (400MHz, CD₃OD) δ ppm 8.01-7.97 (d, J=15.2 Hz, 1 H), 7.69-7.65 (m, 3 H),7.55-7.41 (m, 3 H), 5.92-5.91 (d, J=2.4 Hz, 2 H), 5.02-4.92 (m, 2 H),4.31-4.10 (m, 2 H), 3.83-3.60 (m, 1 H), 3.41-3.32 (m, 1 H), 2.69-2.63(m, 2 H), 2.45-2.43 (m, 3 H), 2.38-2.32 (m, 1 H), 2.19-2.11 (m, 1 H),2.10-1.98 (m, 2 H), 1.70-1.65 (m, 2 H), 1.44-1.29 (m, 2 H).

Example 111-8N′-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-N,N-dimethylethane-1,2-diamine

The title compound was prepared in analogy to Example 111-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand N,N-dimethylethane-1,2-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR(400 MHz, CDCl₃) δ ppm 7.61 (s, 2 H), 7.59 (s, 1 H), 7.46-7.44 (d, J=8.4Hz, 1 H), 7.37-7.42 (m, 1 H), 7.31-7.29 (m, 2 H), 5.93 (s, 1 H), 4.88(s, 2 H), 4.25 (m, 2 H), 3.45-3.41 (t, J=6.4 Hz, 2 H), 2.69-2.65 (t,J=6.4 Hz, 2 H), 2.53-2.44 (m, 2 H), 2.39 (s, 3 H), 2.34 (s, 3 H).

Example 111-9N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]propane-1,3-diamine

The title compound was prepared in analogy to Example 111-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand propane-1,3-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 397, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.60-7.52 (m, 3 H), 7.40-7.32 (t, J=2.4 Hz, 2 H), 7.30-7.20(m, 2 H), 5.92 (s, 1 H), 4.30-4.20 (m, 2 H), 3.38-3.30 (t, J=6.8 Hz, 2H), 2.81-2.74 (t, J=7.2 Hz, 2 H), 2.51-2.40 (m, 2 H), 2.37 (s, 3 H),1.90-1.80 (m, 2 H), 1.32-1.25 (m, 2 H).

Example 111-10N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]butane-1,4-diamine

The title compound was prepared in analogy to Example 111-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand butane-1,4-diamine. MS obsd. (ESI⁺) [(M+H)⁺] 411, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.60-7.52 (m, 3 H), 7.40-7.35 (t, J=2.4 Hz, 2 H), 7.32-7.20(m, 2 H), 5.90 (s, 1 H), 4.30-4.20 (m, 2 H), 3.35-3.25 (m, 2 H),2.78-2.68 (t, J=7.2 Hz, 2 H), 2.51-2.40 (m, 2 H), 2.37 (s, 3 H),1.78-1.68 (m, 2 H), 1.68-1.58 (m, 2 H), 1.32-1.25 (m, 2 H).

Example 111-11trans-4-Amino-1-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol

The title compound was prepared in analogy to Example 111-1 in Scheme 56by using2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepineand tert-butyl [(3S,4S)-4-hydroxypyrrolidin-3-yl]carbamate. MS obsd.(ESI⁺) [(M+H)⁺] 425, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.75 (s, 1 H),7.65-7.55 (m, 2 H), 7.50-7.40 (d, J=7.6 Hz, 1 H), 7.42-7.35 (t, 1 H),7.35-7.25 (m, 2 H), 5.60 (s, 1 H), 4.80 (s, 2 H), 4.60-4.50 (m, 1 H),4.25-4.15 (m, 1 H), 4.15-4.00 (m, 3 H), 3.90-3.80 (m, 1 H), 3.80-3.70(m, 1 H), 3.65-3.55 (m, 1 H), 3.30 (s, 2 H), 2.60-2.40 (m, 2 H), 2.30(s, 3 H).

Example 112-1N-{[3-(Aminomethyl)-1,1-dioxidothietan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine

A mixture solution of2-(4-chloro-6-methyl-quinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine(218 mg, 0.609 mmol), (1,1-dioxidothietane-3,3-diyl)dimethanamine (110mg, 0.670 mmol), (tris(dibenzylideneacetone) dipalladium(0) (56 mg,0.061 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (38 mg,0.061 mmol) and sodium tert-butoxide (117 mg, 1.218 mmol) in toluene (5mL) was heated at 110° C. overnight. The resulting reaction mixture waspoured into water (10 mL) and extracted with dichloromethane (20 mL×3),The combined organic layers were dried over sodium sulfate andconcentrated in vacuo. The residue was purified by flash columnchromatography and preparative HPLC to afford 50 mg of the product as awhite solid (yield was 17%). MS obsd. (ESI⁺) [(M+H)⁺] 487, ¹H NMR (400MHz, CD₃OD) δ ppm 7.970 (s, 1 H), 7.751-7.703 (m, 3 H), 7.618-7.593 (dd,J=8.8, 1.2 Hz, 1 H), 7.533-7.497 (m, 2 H), 6.377 (s, 1 H), 5.107 (s, 1H), 4.315-4.106 (m, 6 H), 3.993 (s, 1 H), 3.569 (s, 1 H), 2.708-2.645(m, 2 H), 2.479 (s, 3 H).

Example 112-2N-[(3-Aminooxetan-3-yl)methyl]-2-[(5E)-5-(methoxyimino)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]-6-methylquinolin-4-amine

(5E)-2-(4-Chloro-6-methylquinolin-2-yl)-N-methoxy-1,2,3,4-tetrahydro-5H-2-benzazepin-5-imine

The title compound was prepared in analogy to2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepinein Example 110-1 in Scheme 56 by using 2,4-dichoro-6-methylquinoline andN-methoxy-1,2,3,4-tetrahydro-5H-2-benzazepin-5-imine.N-[(3-Aminooxetan-3-yl)methyl]-2-[(5E)-5-(methoxyimino)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]-6-methylquinolin-4-amine

The title compound was prepared in analogy to Example 112-1 in Scheme 56by using(5E)-2-(4-chloro-6-methylquinolin-2-yl)-N-methoxy-1,2,3,4-tetrahydro-5H-2-benzazepin-5-imineand 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 432, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.965 (s, 1 H), 7.706-7.684 (d, J=8.8 Hz, 1 H),7.609-7.586 (m, 3 H), 7.453-7.376 (m, 2 H), 6.100 (s, 1 H), 5.035 (s, 2H), 4.695-4.623 (m, 4 H), 4.014-3.987 (m, 4 H), 3.928 (s, 3 H),3.258-3.242 (m, 2 H), 2.471 (s, 3 H).

Example 113N-{2-[(2-Aminoethyl)sulfonyl]ethyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine

N-{2-[(2-Aminoethyl)sulfanyl]ethyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine

A mixture of2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine(160 mg, 0.447 mmol) and 2-[(2-aminoethyl)sulfanyl]ethan-1-amine (1.5mL) was heated at 150° C. for 8 hours. The resulting reaction mixturewas concentrated in vacuo. The residue was dissolved in dichloromethane(20 mL), washed with a saturated aqueous solution of sodium bicarbonate(20 mL) and brine (20 mL), dried over sodium sulfate and concentrated invacuo. The residue was purified by flash column chromatography (elutingwith 10-20% methanol in dichloromethane) to afford 180 mg of the desiredproduct as oil (yield was 91.1%), MS obsd. (ESI⁺) [(M+H)⁺] 443.

N-{2-[(2-Aminoethyl)sulfonyl]ethyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine

To a solution ofN-{2-[(2-aminoethyl)sulfanyl]ethyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine(120 mg, 0.271 mmol) in acetic acid (2 mL) was added potassiumpermanganate (60 mg, 0.38 mmol). After being stirred at room temperaturefor 30 minutes, the resulting mixture was concentrated in vacuo. Theresidue was purified by preparative HPLC to afford 5 mg of the desiredproduct as a solid. MS obsd. (ESI⁺) [(M+H)⁺] 475, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.81 (s, 1 H), 7.77-7.68 (m, 2 H), 7.676 (s, 1 H), 7.56(dd, J=7.2, 1.2 Hz, 2 H), 7.47 (t, J=7.6 Hz, 1 H), 6.08 (s, 1 H), 5.07(brs, 2 H), 4.60 (brs, 2 H), 4.27 (t, J=5.6 Hz, 2 H), 4.01 (t, J=6.4 Hz,2 H), 3.62 (t, J=6.8 Hz, 2 H), 3.53 (m, 2 H), 3.42 (m, 2 H), 2.48 (s, 3H).

Example 114-12-(4-{[(3-Aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-1,2,3,4-tetrahydro-5H-2-benzazepin-5-one

2-(4-Hydroxy-6-methylquinazolin-2-yl)-1,2,3,4-tetrahydro-5H-2-benzazepin-5-one

To a stirred solution of 2-chloro-4(3H)-quinazolinone (580 mg, 3.0 mmol)and 1,2,3,4-tetrahydro-5H-2-benzazepin-5-one (591 mg, 3.0 mmol) intoluene (20 mL) was added triethylamine (626 μL, 4.5 mmol). After beingrefluxed overnight, the resulting reaction mixture was cooled and theformed solid was collected by filtration, washed with ethanol (10 mL)and ethyl acetate (10 mL), and dried in vacuo to afford 775 mg of thedesired product as a white solid (yield was 81%).

2-(4-{[(3-Aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-1,2,3,4-tetrahydro-5H-2-benzazepin-5-one

The title compound was prepared in analogy to Example 62-1 in Scheme 23by using2-(4-hydroxy-6-methylquinazolin-2-yl)-1,2,3,4-tetrahydro-5H-2-benzazepin-5-oneand 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 404, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.94 (s, 1 H), 7.90 (d, 1 H), 7.75 (d, 1 H),7.65-7.55 (m, 3 H), 7.45 (t, 1 H), 5.40 (s, 2 H), 4.77-7.72 (m, 4 H),4.40 (s, 2 H), 4.05 (brs, 2 H), 3.35 (t, 2 H), 2.43 (s, 3 H).

Example 114-2N-{[3-(Aminomethyl)thietan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine

The title compound was prepared in analogy to Example 114-1 in Scheme 23by using 2-chloro-4(3H)-quinazolinone,5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine andthietane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 456, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.701-7.683 (d, J=7.2 Hz, 1 H), 7.605 (s, 1 H),7.574-7.554 (d, J=8.0 Hz, 1 H), 7.392-7.336 (m, 2 H), 7.298-7.251 (t,J=8.4, 10.4 Hz, 2 H), 4.990 (s, 2 H), 4.309-4.283 (t, J=4.8, 5.6 Hz, 2H), 4.035 (s, 2 H), 3.119-3.095 (d, J=9.6 Hz, 2 H), 3.016-2.992 (d,J=9.6 Hz, 2 H), 2.849 (s, 2 H), 2.478-2.413 (m, 2 H), 2.356 (s, 3 H).

Example 114-3N-{[3-(Aminomethyl)oxetan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine

The title compound was prepared in analogy to Example 114-1 in Scheme 23by using 2-chloro-4(3H)-quinazolinone,5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine andoxetane-3,3-diyldimethanamine. MS obsd. (ESI⁺) [(M+H)⁺] 440, ¹H NMR (400MHz, CD₃OD) δ ppm 8.00 (s, 1 H), 7.67 (m, 3 H), 7.56 (d, 1 H), 7.45 (m,2 H), 5.14 (s, 2 H), 4.64 (d, 2 H), 4.58 (d, 2 H), 4.21 (s, 4 H), 3.41(s, 2 H), 2.63 (brs, 2 H), 2.44 (s, 3 H).

Example 114-42-(Aminomethyl)-2-({[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-yl]amino}methyl)propane-1,3-diol

The title compound was formed when purification of Example 114-3 bypreparative HPLC in acid condition. MS obsd. (ESI⁺) [(M+H)⁺] 458, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.96 (s, 1 H), 7.63-7.75 (m, 4 H), 7.50 (t, 1 H),7.43 (t, 1 H), 5.17 (s, 2 H), 4.27 (s, 2 H), 3.94 (s, 2 H), 3.76 (m, 4H), 3.25 (s, 2 H), 2.68 (s, 2 H), 2.45 (s, 3 H).

Example 1152-(4-{[(3-Aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-ol

2-(5-Hydroxy-5-methyl-1,3,4,5-tetrahydro-benzoazepin-2-yl)-6-methyl-3H-quinazolin-4-one

To a suspension of2-(4-hydroxy-6-methylquinazolin-2-yl)-1,2,3,4-tetrahydro-5H-2-benzazepin-5-one(500 mg, 1.57 mmol) in tetrahydrofuran (15 mL), a solution of methylmagnesium bromide in tetrahydrofuran (3 M, 0.57 ml, 1.72 mmol) was addedat 0° C. The reaction mixture was heated at 50° C. for 4 hours, and thenpoured into a saturated aqueous solution of ammonium chloride (10 mL)and stirred for 10 minutes. The resulting mixture was extracted withdichloromethane (15 mL×3). The combined organic layers were dried oversodium sulfate and concentrated in vacuo. The residue was purified byflash column chromatography (eluting with 50% ethyl acetate in hexanes)to afford 350 mg of the desired product as a white solid (yield was66.5%).

2-(4-{[(3-Aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-ol

The title compound was prepared in analogy to Example 114-1 in Scheme 57by using2-(5-hydroxy-5-methyl-1,3,4,5-tetrahydro-benzoazepin-2-yl)-6-methyl-3H-quinazolin-4-oneand 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI⁺) [(M+H)⁺] 420, ¹H NMR(400 MHz, CD₃OD) δ ppm 7.95 (s, 1 H), 7.66 (d, 2 H), 7.57 (d, 1 H), 7.51(d, 1 H), 7.30 (m, 2 H), 5.31 (d, 2 H), 4.80 (m, 4 H), 4.73 (d, 2 H),4.39 (brs, 2 H), 3.97 (brs, 2 H), 2.45 (s, 3 H), 1.64 (s, 3 H).

Example 116-1N-[(3-Aminooxetan-3-yl)methyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine

2-Chloro-N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-ethylquinazolin-4-amine

A solution of 2,4-dichloro-6-methylquinazoline (1.0 g, 4.69 mmol) inmethanol (10 mL) was added 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine(1.4 g, 5.16 mmol, 60% purity) and triethylamine (0.1 g, 1 mmol). Afterbeing stirred at room temperature overnight, the mixture wasconcentrated in vacuo. The residue was purified by flash columnchromatography (eluting with 20% ethyl acetate in petroleum ether) toafford 1.6 g of the product as a white solid (yield was 76%).

N-{[3-(Dibenzylamino)oxetan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine

To a solution of2-chloro-N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-methylquinazolin-4-amine(200 mg, 0.436 mmol) in N,N-dimethylformamide (3 mL) was added5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepine (80 mg, 0.436 mmol) andtriethylamine (89 mg, 0.872 mmol). The mixture was heated at 120° C. for30 minutes under microwave irradiation. The reaction was poured intowater (10 mL) and extracted with dichloromethane (15 mL×3). The combinedorganic layers were dried over sodium sulfate and concentrated in vacuo.The residue was purified by flash column chromatography (eluting with20% ethyl acetate in petroleum ether) to afford 190 mg of the product asa brown solid (yield was 72%).

N-[(3-Aminooxetan-3-yl)methyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine

A solution ofN-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine(190 mg, 0.314 mmol) and trifluororacetic acid (1 drop) in methanol wasstirred in the presence of palladium hydroxide on carbon (50 mg) at roomtemperature under hydrogen atmosphere overnight. The resulting mixturewas filtered, concentrated in vacuo. The residue was purified bypreparative HPLC to afford 32 mg of the product as a white solid (yieldwas 24%). MS obsd. (ESI⁺) [(M+H)⁺] 426, ¹H NMR (400 MHz, CD₃OD) δ ppm7.696 (s, 1 H), 7.654-7.636 (d, J=7.2 Hz, 1 H), 7.607-7.588 (d, J=7.6Hz, 1 H), 7.404-7.367 (m, 2 H), 7.341-7.283 (m, 2 H), 5.011 (s, 2 H),4.683-4.626 (m, 2 H), 4.556-4.540 (d, J=6.4 Hz, 2 H), 4.335-4.307 (t,J=5.6 Hz, 2 H), 4.084 (s, 2 H), 5.528-2.432 (m, 2 H), 2.398 (s, 3 H).

Example 116-2N-[(3-Amino-1,1-dioxidothietan-3-yl)methyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine

The title compound was prepared in analogy to Example 116-1 in Scheme 57by using 2,4-dichloro-6-methylquinazoline,3-(aminomethyl)-N,N-dibenzyl(1,1-dioxido)thietan-3-amine and5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepine. MS obsd. (ESI⁺)[(M+H)⁺] 474, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.73 (s, 1 H), 7.65 (d, 1H), 7.60 (d, 1 H), 7.29-7.45 (m, 4 H), 5.02 (s, 2 H), 4.04-4.62 (m, 2H), 4.34 (t, 2 H), 4.12 (t, 2 H), 4.01-4.04 (m, 2 H), 2.47 (m, 2 H),2.41 (s, 3 H).

Example 117N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-yl]-2,2-difluoropropane-1,3-diamine

N-(2-Chloro-6-methylquinazolin-4-yl)-2,2-difluoropropane-1,3-diamine

To a solution of 2,2-difluoropropane-1,3-diamine (1.1 g, 10 mmol) andtriethylamine (1.4 mL, 10 mol) in dichloromethane (15 mL) was added asolution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.36 mmol) indichloromethane (5 mL) dropwise. After being stirred at room temperatureovernight, the resulting mixture was poured into water (50 mL) andextracted with dichloromethane (50 mL×2). The combined organic layerswere washed with brine (50 mL), dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by flash columnchromatography (eluting with 10-25% methanol in dichloromethane) toafford 41.8 mg of the desired product as a white solid (yield was 62%).MS obsd. (ESI⁺) [(M+H)⁺] 287.

N-[2-(5,5-Difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-yl]-2,2-difluoropropane-1,3-diamine

A solution ofN-(2-chloro-6-methylquinazolin-4-yl)-2,2-difluoropropane-1,3-diamine (97mg, 0.34 mmol) and 5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine (310mg, 1.70 mmol) in n-butanol (1 mL) was heated at 160° C. for 30 minutes.The resulting reaction mixture was purified by preparative HPLC toafford 24.3 mg of the desired compound as a white solid. MS obsd. (ESI⁺)[(M+H)⁺] 434, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.96 (s, 1 H), 7.68 (d,J=7.2 Hz, 2 H), 7.58 (m, 2 H), 7.46 (m, 2 H), 5.12 (s, 2 H), 4.36 (t,J=13.6 Hz, 2 H), 4.23 (s, 2 H), 3.58 (t, J=16 Hz, 2 H), 2.67 (brs, 2 H),2.44 (s, 3 H).

Example 118-1N-[2-(7-Bromo-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-chloroquinolin-4-yl]ethane-1,2-diamine

7-Bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one

To a cooled solution of 6-bromo-3,4-dihydro-1H-naphthalen-2-one (100 g,0.44 mol) in toluene was added sodium azide (150 g, 2.2 mol) followed byaddition of trifluoromethanesulfonic acid (200 mL) dropwise. When theaddition was completed, the ice bath was removed and the mixture wasstirred at room temperature overnight. The reaction was poured intoice-water, basified with potassium carbonate to pH >10 slowly, and thenextracted with dichloromethane (1000 mL×3). The organic layers werecombined and dried over sodium sulfate, and then concentrated underreduced pressure to give a residue which was separated by columnchromatography on silica gel to give 35 g of crude product. It was usedfor next step without further purification. MS obsd. (ESI⁺) [(M+H)⁺]240.

7-Bromo-2,3,4,5-tetrahydro-1H-2-benzazepine

To a solution of 7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one (35 g,146 mmol) in 1,2-dimethoxyethane (400 mL) was added a solution of boranedimethyl sulfide complex (1.0 M in tetrahydrofuran, 40 mL) undernitrogen and the resulting mixture was stirred under reflux overnight.The reaction was quenched with methanol, acidified with 2 M hydrochloricacid and then stirred for further 2 hours. The resulting mixture wasconcentrated in vacuo and the residue was purified by preparative HPLCto give 4.6 g of product. MS obsd. (ESI⁺) [(M+H)⁺] 226. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.21 (d, J=5 Hz, 1 H), 7.15-7.13 (dd, J=2.0, 8.0 Hz, 1 H),6.89 (d, J=8 Hz, 1 H), 3.79 (s, 2 H), 3.11-3.08 (m, 2 H), 2.82-2.79 (m,2 H), 2.38 (brs, 1 H), 1.63-1.61 (m, 2 H).

7-Bromo-2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine

The mixture of 2,4,6-trichloroquinoline (300 mg, 1.29 mmol),7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine (291 mg, 1.29 mmol) andn-butanol (3 mL) was heated with stirring in a 10 mL microwave processvial for 1 hour at 160° C. under microwave irradiation. The mixture wascooled to room temperature and diluted with ethyl acetate (10 mL), andthen washed with water (10 mL). The organic layer was dried over sodiumsulfate and evaporated to give a residue which was purified by columnchromatography on silica gel to give 222 mg of product as a white solid(yield was 41%). MS obsd. (ESI⁺) [(M+H)⁺] 421.

N-[2-(7-Bromo-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-chloroquinolin-4-yl]ethane-1,2-diamine

The mixture of7-bromo-2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine(200 mg, 0.47 mmol) and ethane-1,2-diamine (0.5 mL) was heated withstirring in a 5 mL microwave process vial for 2 hours at 160° C. undermicrowave irradiation. The solvent was removed under reduced pressure,and the residue was purified by preparative HPLC to give 38 mg ofproduct (yield was 18%). MS obsd. (ESI⁺) [(M+H)⁺] 445, ¹H NMR (400 MHz,CD₃OD) δ ppm 7.90 (d, J=2.4 Hz, 1 H), 7.49 (d, J=8.8 Hz, 1 H), 7.41 (m,1 H), 7.35 (m, 1 H), 7.31 (m, 2 H), 5.99 (s, 1 H), 4.80 (s, 2 H), 4.13(m, 2 H), 3.40 (m, 2 H), 3.00 (m, 4 H), 1.90 (m, 2 H).

Example 118-22-{4-[(2-Aminoethyl)amino]quinolin-2-yl}-2,3,4,5-tetrahydro-1H-2-benzazepin-8-ol

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine-8-ol (commercial available)and 2,4-dichloroquinoline (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 349. ¹H NMR (400 MHz, CD₃OD) δppm 7.82 (d, J=8.0 Hz, 1 H), 7.55 (d, J=8.0 Hz, 1 H), 7.43 (m, 1 H),7.13 (m, 1 H), 6.96 (m, 2 H), 6.56 (m, 1 H), 6.00 (s, 1 H), 4.72 (s, 2H), 4.13 (m, 2 H), 3.43 (t, J=6.4 Hz, 2 H), 2.96 (m, 4 H), 1.87 (m, 2H).

Example 118-3N-[6-Methyl-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and2,4-dichloro-6-methylquinoline (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 347. ¹H NMR (400 MHz, DMSO-d6) δppm 7.68 (s, 1 H), 7.55 (d, J=6.8 Hz, 1 H), 7.29 (d, J=8.4 Hz, 1 H),7.21 (d, J=6.8 Hz, 1 H), 7.13-7.05 (m, 3 H), 6.67 (brs, 1 H), 6.00 (s, 1H), 4.79 (s, 2 H), 4.11 (brs, 2 H), 3.52 (s, 2 H), 3.05-2.99 (m, 4 H),2.35 (s, 3 H), 1.77 (s, 2 H).

Example 118-4N-[2-(8-Fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 8-fluoro-2,3,4,5-tetrahydro-1H-2-benzazepine (commercialavailable) and 2,4-dichloro-6-methylquinoline (commercial available)instead of 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and2,4,6-trichloroquinoline respectively. MS obsd. (ESI⁺) [(M+H)⁺] 365. ¹HNMR (400 MHz, CD₃OD) δ ppm 7.68 (s, 1 H), 7.48 (d, J=8.4 Hz, 1 H), 7.28(m, 2 H), 7.12 (m, 1 H), 6.83 (m, 1 H), 5.93 (s, 1 H), 4.80 (s, 2 H),4.09 (s, 2 H), 3.46 (t, J=6.0 Hz, 2 H), 3.00 (m, 4 H), 2.40 (s, 3 H),1.90 (m, 2 H).

Example 118-5N-[6-Chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available)instead of 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine. MS obsd. (ESI⁺)[(M+H)⁺] 367. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.87 (d, J=2.4 Hz, 1 H),7.47-7.42 (m, 2 H), 7.34 (dd, J=9.0, 2.2 Hz, 1 H), 7.15-7.09 (m, 3 H),5.99 (s, 1 H), 4.76 (s, 2 H), 4.11 (brs, 2 H), 3.38-3.32 (m, 2 H),3.00-2.93 (m, 4 H), 1.87 (t, J=5.2 Hz, 2 H).

Example 118-6N-[6-Chloro-2-(9-fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 9-fluoro-2,3,4,5-tetrahydro-1H-2-benzazepine (commercialavailable) instead of 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine. MSobsd. (ESI⁺) [(M+H)⁺] 385. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.90 (d, J=2.0Hz, 1 H), 7.47 (d, J=8.8 Hz, 1 H), 7.36 (dd, J=8.8, 2.4 Hz, 1 H), 7.13(m, 1H), 7.00 (m, 2 H), 6.11 (s, 1 H), 4.91 (s, 2 H), 4.21 (s, 2 H),3.45 (t, J=6.0 Hz, 2 H), 3.10 (m, 2 H), 3.00 (t, J=6.0 Hz, 2 H), 1.89(m, 2 H).

Example 118-7N-[2-(8-Fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 8-fluoro-2,3,4,5-tetrahydro-1H-2-benzazepine (commercialavailable) and 2,4-dichloroquinoline (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 351. ¹H NMR (400 MHz, CD₃OD) δppm 7.90 (d, J=7.6 Hz, 1 H), 7.58 (d, J=8.0 Hz, 1 H), 7.52 (t, J=6.8,1.2 Hz, 1 H), 7.19 (m, 2 H), 7.02 (m, 2 H), 6.07 (s, 1 H), 4.21 (s, 2H), 3.52 (t, J=6.0 Hz, 2 H), 4.91 (s, 2 H), 3.12 (m, 2 H), 3.06 (m, 2H), 1.94 (m, 2 H).

Example 118-81-Amino-3-{[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-oltrifluoroacetate (salt)

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available),2,4-dichloroquinoline (commercial available) and 1,3-diamino-propan-2-ol(commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine, 2,4,6-trichloroquinolineand ethane-1,2-diamine respectively. MS obsd. (ESI⁺) [(M+H)⁺] 363. ¹HNMR (400 MHz, CD₃OD CD₃OD) δ ppm 8.05-8.03 (d, J=7.6 Hz, 1 H), 7.78-7.76(d, J=7.6 Hz, 1 H), 7.72-7.68 (m, 1 H), 7.52-7.50 (m, 1 H), 7.44-7.40(m, 1 H), 7.23-7.19 (m, 3 H), 6.12 (s, 1 H), 4.97 (s, 2 H), 4.16-4.11(m, 3 H), 3.56-3.55 (d, J=6 Hz, 2 H), 3.20-3.16 (dd, J=2.8, 12.8 Hz, 1H), 3.11-3.08 (m, 2 H), 2.99-2.94 (m, 1 H), 1.99-1.98 (m, 2 H).

Example 118-9N-[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and2,4-dichloroquinoline (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 333. ¹H NMR (400 MHz, CD₃OD) δppm 7.91-7.89 (m, 1 H), 7.62-7.60 (m, 1 H), 7.52-7.45 (m, 2 H),7.21-7.12 (m, 3 H), 5.96 (s, 1 H), 4.10 (s, 2 H), 3.51-3.47 (t, J=6.0Hz, 1 H), 3.04-2.98 (m, 5 H), 2.84 (s, 2 H), 1.94-1.91 (m, 2 H).

Example 118-10N-[6-Bromo-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and6-bromo-2,4-dichloroquinoline (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 411. ¹H NMR (400 MHz, CD₃OD) δppm 8.05 (d, J=2.0 Hz, 1 H), 7.52-7.42 (m, 3 H), 7.16-7.12 (m, 3 H),6.03 (s, 1 H), 4.83 (s, 2 H), 4.15 (brs, 2 H), 3.48 (t, J=6.0 Hz, 2 H),3.07-3.03 (m, 4 H), 1.94 (t, J=5.2 Hz, 2 H).

Example 118-11N-[6-Methoxy-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and2,4-dichloro-6-methoxyquinoline (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 363. ¹H NMR (400 MHz, CD₃OD) δppm 7.60 (d, J=9.2 Hz, 1 H), 7.50 (d, J=6.4 Hz, 1 H), 7.42 (d, J=2.4 Hz,1 H), 7.25-7.18 (m, 4 H), 6.01 (s, 1 H), 4.93 (s, 2 H), 4.13 (brs, 2 H),3.89 (s, 3 H), 3.53 (t, J=6.4 Hz, 2 H), 3.10-3.01 (m, 4 H), 1.96 (s, 2H).

Example 118-12N-[2-(6-Chloro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 5-chloro-3,4-dihydro-1H-naphthalen-2-one (commercial available)and 2,4-dichloroquinoline (commercial available) instead of6-bromo-3,4-dihydro-1H-naphthalen-2-one and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 367. ¹H NMR (400 MHz, CD₃OD) δppm 7.82 (d, J=8.0 Hz, 1 H), 7.53 (d, J=8.4 Hz, 1 H), 7.43 (m, 2 H),7.25 (d, J=8.4 Hz, 1 H), 7.12 (m, 2 H), 5.96 (s, 1 H), 4.87 (s, 2 H),4.10 (s, 2 H), 3.41 (m, 2 H), 3.25 (m, 2 H), 2.95 (m, 2 H), 1.94 (m, 2H).

Example 118-13N-[2-(7-Fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 6-fluoro-3,4-dihydro-1H-naphthalen-2-one (commercial available)and 2,4-dichloro-6-methylquinoline (commercial available) instead of6-bromo-3,4-dihydro-1H-naphthalen-2-one and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 365. ¹H NMR (400 MHz, CD₃OD) δppm 7.82 (s, 1 H), 7.58 (d, J=8.4 Hz, 1 H), 7.45 (m, 1 H), 7.17 (m, 1H), 6.94 (m, 1 H), 6.84 (m, 1 H), 6.03 (d, J=4.0 Hz, 1 H), 4.87 (s, 2H), 3.95 (m, 4 H), 3.56 (t, J=6.4 Hz, 2 H), 3.10 (m, 4 H), 2.48 (s, 3H).

Example 118-14N-Methyl-N′-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available),2,4-dichloroquinoline (commercial available) andN-methyl-ethane-1,2-diamine (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine, 2,4,6-trichloroquinolineand ethane-1,2-diamine respectively. MS obsd. (ESI⁺) [(M+H)⁺] 347. ¹HNMR (400 MHz, DMSO-d6) δ ppm 8.42 (brs, 2 H), 7.88 (s, 1 H), 7.55 (d,J=6.4 Hz, 1 H), 7.47 (s, 2 H), 7.16-7.11 (m, 4 H), 6.01 (s, 1 H), 4.87(s, 2 H), 4.14 (s, 2 H), 3.63 (s, 2 H), 3.20 (t, J=5.6 Hz, 2 H), 3.02(s, 2 H), 2.67 (s, 3 H), 1.80 (s, 2 H).

Example 118-15N-[2-(7-Methoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 7-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepine (commercialavailable) and 2,4-dichloroquinoline (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 363. ¹H NMR (400 MHz, CD₃OD) δppm 8.00 (d, J=6.0 Hz, 1 H), 7.70 (d, J=8.0 Hz, 1 H), 7.63 (t, J=6.0 Hz,1 H), 7.43 (d, J=8.0 Hz, 1 H), 7.34 (m, 1 H), 6.80 (m, 1 H), 6.76 (m, 1H), 6.00 (s, 1 H), 4.87 (s, 2 H), 4.13 (m, 2 H), 3.76 (s, 3 H), 3.59 (m,2 H), 3.09 (m, 4 H), 1.97 (m, 2 H).

Example 118-16N-[2-(7-Fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 6-fluoro-3,4-dihydro-1H-naphthalen-2-one (commercial available)and 2,4-dichloroquinoline (commercial available) instead of6-bromo-3,4-dihydro-1H-naphthalen-2-one and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 351. ¹H NMR (400 MHz, CD₃OD) δppm 7.92 (d, J=8.4 Hz, 1 H), 7.63 (d, J=8.0 Hz, 1 H), 7.55-7.49 (m, 2H), 7.24 (m, 1 H), 6.96-6.91 (m, 2 H), 5.97 (s, 1 H), 4.86 (s, 2 H),4.12 (s, 2 H), 3.55 (t, J=6.0 Hz, 2 H), 3.08 (m, 4 H), 1.95 (m, 2 H).

Example 118-17N-[2-(8-Methoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 591 by using 8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepine (commercialavailable) and 2,4-dichloroquinoline (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 363. ¹H NMR (400 MHz, CD₃OD) δppm 8.08 (d, J=8.4 Hz, 1 H), 7.82 (d, J=8.0 Hz, 1 H), 7.75 (t, J=7.2 Hz,1 H), 7.46 (t, J=8.0 Hz, 1 H), 7.19 (m, 1 H), 7.13 (m, 1 H), 6.81 (m, 1H), 6.05 (s, 1 H), 4.96 (s, 2 H), 4.15 (m, 2 H), 3.82 (m, 5 H), 3.29 (m,2 H), 3.07 (m, 2 H), 1.99 (m, 2 H).

Example 118-18N-[6-(Difluoromethoxy)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and2,4-dichloro-6-difluoromethoxyquinoline (commercial available) insteadof 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and2,4,6-trichloroquinoline respectively. MS obsd. (ESI⁺) [(M+H)⁺] 399. ¹HNMR (400 MHz, CD₃OD) δ ppm 7.63 (d, J=2.4 Hz, 1 H), 7.55 (d, J=9.2 Hz, 1H), 7.47 (d, J=6.8 Hz, 1 H), 7.27 (dd, J=8.8, 2.4 Hz, 1 H), 7.18-7.12(m, 3 H), 6.79 (t, J=74.4 Hz, 1 H, HCF₂O—), 6.03 (s, 1 H), 4.82 (s, 2H), 4.15 (brs, 2 H), 3.46 (t, J=6.2 Hz, 2 H), 3.06-3.00 (m, 4 H), 1.91(t, J=5.2 Hz, 2 H).

Example 118-19N-[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)-6-(trifluoromethyl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and2,4-dichloro-6-trifluoromethylquinoline (commercial available) insteadof 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and2,4,6-trichloroquinoline respectively. MS obsd. (ESI⁺) [(M+H)⁺] 401. ¹HNMR (400 MHz, DMSO-d6) δ ppm 8.36 (s, 1 H), 7.57-7.45 (m, 3 H), 7.12(brs, 3 H), 6.99 (s, 1 H), 6.03 (s, 1 H), 4.81 (s, 2 H), 4.15 (brs, 2H), 3.29 (brs, 2 H), 3.01 (s, 2 H), 2.82 (s, 2 H), 1.77 (s, 2 H).

Example 118-20N-[8-Chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and2,4,8-trichloroquinoline (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 367. ¹H NMR (400 MHz, CD₃OD) δppm 7.24 (d, J=8.0 Hz, 1 H), 7.60 (d, J=6.8 Hz, 1 H), 7.55 (d, J=7.6 Hz,1 H), 7.13-7.09 (m, 3 H), 6.98 (t, J=8.0 Hz, 1 H), 6.03 (s, 1 H), 4.89(s, 2 H), 4.20 (brs, 2 H), 3.46 (t, J=6.0 Hz, 2 H), 3.07-3.02 (m, 4 H),1.92 (t, J=5.2 Hz, 2 H).

Example 118-21N-[6-Fluoro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and2,4-dichloro-6-fluoroquinoline (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 351. ¹H NMR (400 MHz, CD₃OD) δppm 7.60-7.52 (m, 2 H), 7.47 (d, J=6.8 Hz, 1 H), 7.26-7.21 (m, 1 H),7.17-7.12 (m, 3 H), 6.04 (s, 1 H), 4.82 (s, 2 H), 4.15 (brs, 2 H), 3.45(t, J=6.4 Hz, 2 H), 3.06-2.99 (m, 4 H), 1.91 (t, J=5.4 Hz, 2 H).

Example 118-22N,N-Dimethyl-N′-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available),2,4-dichloroquinoline (commercial available) andN,N-dimethyl-ethane-1,2-diamine (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine, 2,4,6-trichloroquinolineand ethane-1,2-diamine respectively. MS obsd. (ESi⁺) [(M+H)⁺] 361. ¹HNMR (400 MHz, DMSO-d6) δ ppm 7.90 (d, J=3.6 Hz, 1 H), 7.56-7.46 (m, 3H), 7.15-7.11 (m, 4 H), 5.89 (s, 1 H), 4.87 (s, 2 H), 4.14 (s, 2 H),3.53 (s, 2 H), 3.05 (s, 2 H), 2.91 (s, 2 H), 2.53 (s, 6 H), 1.80 (s, 2H).

Example 118-23N-[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)-6-(trifluoromethoxy)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and2,4-dichloro-6-trifluoromethoxyquinoline (commercial available) insteadof 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and2,4,6-trichloroquinoline respectively. MS obsd. (ESI⁺) [(M+H)⁺] 417. ¹HNMR (400 MHz, CD₃OD) δ ppm 7.80 (d, J=2.0 Hz, 1 H), 7.56 (d, J=9.2 Hz, 1H), 7.48 (d, J=6.8 Hz, 1 H), 7.33 (d, J=10.0 Hz, 1 H), 7.18-7.12 (m, 3H), 6.06 (s, 1 H), 4.83 (s, 2 H), 4.16 (brs, 2 H), 3.46 (t, J=6.2 Hz, 2H), 3.06-3.00 (m, 4 H), 1.91 (t, J=5.2 Hz, 2 H).

Example 118-24N-[6-(Methylsulfonyl)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and2,4-dichloro-6-methanesulfonylquinoline (commercial available) insteadof 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and2,4,6-trichloroquinoline respectively. MS obsd. (ESI⁺) [(M+H)⁺] 411. ¹HNMR (400 MHz, DMSO-d6) δ ppm 8.518 (s, 0.5 H), 8.514 (s, 0.5 H),7.76-7.73 (m, 1 H), 7.61 (d, J=6.4 Hz, 0.5 H), 7.52 (d, J=6.8 Hz, 0.5H), 7.47-7.34 (m, 1 H), 7.13-7.07 (m, 3 H), 6.23 (s, 0.5 H), 6.04 (s,0.5 H), 4.83 (d, J=6.4 Hz, 2 H), 4.34 (brs, 2 H), 3.15 (brs, 4 H), 3.00(s, 2 H), 2.81 (t, J=6.4 Hz, 1 H), 1.76 (brs, 2 H).

Example 118-252-{4-[(2-Aminoethyl)amino]quinolin-2-yl}-2,3,4,5-tetrahydro-1H-2-benzazepine-8-carboxylicacid

The title compound was prepared in analogy to Example 118-1 in Scheme 59by using 2,3,4,5-tetrahydro-1H-2-benzazepine-8-carboxylic acid(commercial available) and 2,4-dichloroquinoline (commercial available)instead of 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and2,4,6-trichloroquinoline respectively. MS obsd. (ESI⁺) [(M+H)⁺] 377. ¹HNMR (400 MHz, CD₃OD) δ ppm 8.57 (s, 1 H), 8.07 (s, 1 H), 7.84 (d, J=7.6Hz, 1 H), 7.74 (dd, J=6.0 Hz, 1 H), 7.58 (d, J=8.4 Hz, 1 H), 7.47 (m, 1H), 7.18 (m, 2 H), 6.10 (s, 1 H), 4.24 (brs, 2 H), 3.62 (m, 2 H), 3.26(m, 2 H), 3.16 (m, 4 H), 1.91 (m, 2 H).

Example 118-262-(4-Chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine

The title compound was prepared in Scheme 1 by using2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and2,4-dichloroquinoline (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and 2,4,6-trichloroquinolinerespectively. MS obsd. (ESI⁺) [(M+H)⁺] 309. ¹H NMR (400 MHz, CDCl₃) δppm 7.92-7.88 (dd, J=1.2, 8.0 Hz, 1 H), 7.65 (d, J=8 Hz, 1 H), 7.53-7.45(m, 2 H), 7.24-7.10 (m, 5 H), 4.81 (s, 2 H), 4.09 (brs, 2 H), 3.02-2.97(m, 2 H), 1.94-1.88 (m, 2 H).

Example 119N-[5-Chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

1-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)ethanone

A suspension of 2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride (10 g,54.4 mmol) in dry dichloromethane (450 mL) was stirred at 0° C.Triethylamine (18.21 mL, 130.6 mmol) was added followed by the dropwiseaddition of acetic anhydride (6.18 mL, 65.3 mmol) in dry dichloromethane(50 mL). The reaction was then stirred for 1 hour whilst allowing thetemperature to rise slowly to room temperature. The resulting mixturewas washed with 1 N hydrochloric acid (200 mL) and brine (200 mL), driedover sodium sulfate and concentrated in vacuo to give 10 g of product ascolorless oil (yield was 97%). It was used in next step without furtherpurification. MS obsd. (ESI⁺) [(M+H)⁺] 190.

2-Chloro-6-{[1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)ethylidene]amino}benzonitrile

Phosphorus oxychloride (2.93 mL, 32.0 mmol) was added to a stirredsolution of 1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)ethanone (5.5 g,29.0 mmol) in dry dichloromethane (100 mL) at 10° C. After that, themixture was stirred for 20 minutes at room temperature. Then a solutionof 2-amino-6-chloro-benzonitrile (4.43 g, 29.0 mmol) in drydichloromethane (40 mL) was added and the resulting suspension washeated under reflux for 24 hours. After the reaction mixture was cooledto room temperature, water (50 mL) was added followed by saturatedsodium bicarbonate to pH 8. The organic layer was separated and theaqueous was extracted with dichloromethane (100 mL). The organicfraction was washed with brine and dried over sodium sulfate, and thenevaporated in vacuo to give a residue which was precipitated in ether.The solid was collected by filtration and dried in vacuo to give 6 g ofproduct as a brown powder (yield was 63.7%). It was used in the nextstep without further purification. MS obsd. (ESI⁺) [(M+H)⁺] 324.

5-Chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine

The mixture of2-chloro-6-{[1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)ethylidene]amino}benzonitrile(6 g, 18.5 mmol), zinc chloride (2.52 g, 18.5 mmol) andN,N-dimethyl-acetamide (18 mL) was heated with stirring at 160° C. for 3hours under argon. After the reaction was allowed to cool to about 40°C., sodium hydroxide (2 N, 20 mL) was added and then stirred for 10minutes at room temperature. The reaction mixture was poured into waterand the solid was collected by filtration, washed with water and driedin vacuo to give 5 g of product as an off-white powder (yield was83.3%). MS obsd. (ESI⁺) [(M+H)⁺] 324.

2-(4,5-Dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine

To the suspension of5-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine(1.5 g, 4.6 mmol) in concentrated hydrochloric acid (10 mL) was added asolution of sodium nitrite (390 mg, 5.6 mmol) in water at −10° C. Afterthe addition, the reaction mixture was stirred for further 30 minutes,and then sodium chloride (2 g) was added. The resulting mixture wasstirred at room temperature overnight and neutralized with saturatedsodium bicarbonate, extracted with dichloromethane (50 mL×2). Theorganic layers were combined and dried over sodium sulfate, and thenconcentrated under reduced pressure to give the crude product. It wasused in next step without further purification.

N-[5-Chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The mixture of2-(4,5-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepineprepared above and ethane-1,2-diamine (2 mL) was heated with stirring ina 10 mL microwave process vial for 2 hours at 150° C. under microwaveirradiation. The reaction mixture was diluted with ethyl acetate (20mL), and then washed with water (20 mL). The organic fraction was driedover sodium sulfate, and concentrated under reduced pressure to give aresidue which was purified by preparative HPLC to give 20 mg of productas a white powder. MS obsd. (ESI⁺) [(M+H)⁺] 367. ¹H NMR (400 MHz, CD₃OD)δ ppm 7.46-7.42 (m, 2 H), 7.27-7.23 (m, 1 H), 7.16-7.11 (m, 3 H), 7.02(66, J=7.6, 1.2 Hz, 1 H), 5.97 (s, 1 H), 4.79 (s, 2 H), 4.13 (brs, 2 H),3.38-3.21 (m, 2 H), 3.04-3.02 (m, 2 H), 2.96 (t, J=6.0 Hz, 2 H),1.91-1.86 (m, 2 H).

Example 120-1N-{2-[7-(Methylsulfonyl)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]quinolin-4-yl}ethane-1,2-diamine

The mixture of 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine (226 mg, 1.0mmol), sodium methanesulfinate (120 mg, 1.2 mmol), copper(I) iodide (19mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol), sodium hydroxide (8.0 mg,0.2 mmol) and dimethyl sulfoxide (2 mL) was heated in a sealed tube for20 hours at 95° C. The resulting mixture was diluted with water, andextracted with ethyl acetate (30 mL×3). The organic layers were combinedand washed with brine (40 mL×3), and then dried over sodium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedby column chromatography on silica gel (methanol/dichloromethane, 1:20)to give 144 mg of product as a light-brown viscous oil (yield was63.9%). MS obsd. (ESI⁺) [(M+H)⁺] 226.

2-(4-Chloroquinolin-2-yl)-7-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-2-benzazepine

The mixture of 2,4-dichloroquinoline (126 mg, 0.637 mmol),7-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (144 mg, 0.637mmol), triethylamine (0.106 mL, 0.765 mmol) and N-methyl-2-pyrrolidone(2 mL) was heated with stirring in a sealed tube for 4 hours at 100° C.The resulting mixture was diluted with water and extracted with ethylacetate (15 mL×3). The organic layers were combined and washed withbrine (15 mL×3), and then dried over sodium sulfate. The solvent wasremoved under reduced pressure and the residue was purified by columnchromatography on silica gel (ethyl acetate/petroleum ether, 1:5) toafford 55.6 mg of product as a white solid (yield was 22.5%). MS obsd.(ESI⁺) [(M+H)⁺] 387.

N-{2-[7-(Methylsulfonyl)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]quinolin-4-yl}ethane-1,2-diamine

The mixture of2-(4-chloroquinolin-2-yl)-7-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-2-benzazepine(55.6 mg, 0.144 mmol) and ethane-1,2-diamine (1 mL) was heated withstirring in a 10 mL microwave process vial for 2 hours at 150° C. undermicrowave irradiation. The solvent was removed in vacuo and the residuewas purified by preparative HPLC to give 27.5 mg of product as alight-yellow solid (yield was 46.5%). MS obsd. (ESI⁺) [(M+H)⁺] 411. ¹HNMR (400 MHz, CD₃OD) δ ppm 7.82-7.73 (m, 4 H), 7.53 (d, J=7.6 Hz, 1 H),7.45-7.40 (m, 1 H), 7.12-7.08 (m, 1 H), 5.98 (s, 1 H), 4.96 (s, 2 H),4.16 (s, 2 H), 3.41 (t, J=6.4 Hz, 2 H), 3.16 (brs, 2 H), 3.06 (s, 3 H),2.97 (t, J=6.4 Hz, 2 H), 1.96 (brs, 2 H).

Example 120-2N-{2-[7-(Ethylsulfonyl)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]quinolin-4-yl}ethane-1,2-diamine

The title compound was prepared in analogy to Example 120-1 by usingsodium ethanesulfinate (commercial available) instead of sodiummethanesulfinate. MS obsd. (ESI⁺) [(M+H)⁺] 424. ¹H NMR (400 MHz, CD₃OD)δ ppm 7.81-7.76 (m, 2 H), 7.70-7.67 (m, 2 H), 7.53 (d, J=7.6 Hz, 1 H),7.43-7.39 (m, 1 H), 7.10-7.06 (m, 1 H), 5.97 (s, 1 H), 4.93 (s, 2 H),4.14 (s, 2 H), 3.39 (t, J=6.4 Hz, 2 H), 3.16-3.10 (m, 4 H), 2.95 (t,J=6.4 Hz, 2 H), 1.94 (brs, 2 H), 1.16 (t, J=7.2 Hz, 3 H).

Example 121N-[2-(8-Ethoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

2-(4-Chloroquinolin-2-yl)-8-ethoxy-2,3,4,5-tetrahydro-1H-2-benzazepine

To a solution of2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepin-8-ol (36mg, 0.11 mmol) in 5 mL of dry N,N-dimethylformamide was added sodiumhydride (8 mg, 0.17 mmol), then bromoethane (18.5 mg, 0.17 mmol) wasadded dropwise under nitrogen. After the addition, the reaction wasstirred at room temperature for further 1 hour. The resulting mixturewas diluted with dichloromethane (10 mL), washed with brine and thendried over sodium sulfate. The solvent was removed in vacuo and theresidue was purified by column chromatography on silica gel to give 28mg of product. MS obsd. (ESI⁺) [(M+H)⁺] 353.

N-[2-(8-Ethoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The mixture of2-(4-chloroquinolin-2-yl)-8-ethoxy-2,3,4,5-tetrahydro-1H-2-benzazepine(28 mg, 0.79 mmol) and ethane-1,2-diamine (0.5 mL) was heated withstirring in a 5 mL microwave process vial for 2 hours at 160° C. undermicrowave irradiation. The solvent was removed under reduced pressureand the residue was purified by preparative HPLC to give 12 mg ofproduct (yield was 40%). MS obsd. (ESI⁺) [(M+H)⁺] 377. ¹H NMR (400 MHz,CD₃OD) δ ppm 7.88 (d, J=7.6 Hz, 1 H,), 7.62 (d, J=8.0 Hz, 1 H), 7.57 (m,1 H), 7.51 (d, J=8.4 Hz, 1 H), 7.38 (m, 1 H), 7.19 (m, 2 H), 6.00 (s, 1H), 4.78 (s, 2 H), 4.12 (m, 2 H), 3.99 (q, J=6.8 Hz, 2 H), 3.48 (m, 2H), 2.98 (m, 4 H), 1.94 (m, 2 H), 1.34 (t, J=6.8 Hz, 3 H).

Example 122N-[6-(Pyridin-2-yloxy)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

4-Chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-6-ol

To a solution of2-(4-chloro-6-methoxy-quinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine(800 mg, 2.37 mmol) in 15 mL of dichloromethane was added slowly asolution of boron tribromide (0.558 mL, 5.9 mmol). The resulting mixturewas stirred at room temperature for 30 minutes, followed by stirring at40° C. for 2 hours. After cooled to room temperature, the reactionmixture was carefully quenched with sodium bicarbonate (20 mL), and thenextracted with dichloromethane (10 mL×3). The organic layers werecombined and washed with brine (20 ml), then dried over sodium sulfate.The solvent was removed in vacuo and the residue was purified by flashcolumn chromatography on silica gel (ethyl acetate/hexane, 1:5) to give500 mg of product (yield was 65%).

2-[4-Chloro-6-(pyridin-2-yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine

The mixture of4-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-6-ol (200mg, 0.617 mmol), 2-fluoro-pyridine (180 mg, 1.85 mmol), potassiumcarbonate (73 mg, 0.53 mmol) and dry dimethylsulfoxide was heated withstirring in a sealed tube for 40 minutes at 130° C. under microwaveirradiation. The resulting mixture was cooled to room temperature, thendiluted with water (10 mL) and extracted with ethyl acetate (10 mL×2).The combined organic layer was washed with brine (10 mL×3), and thendried over sodium sulfate. The solvent was removed in vacuo and theresidue was purified by column chromatography on silica gel (ethylacetate/petroleum ether, 1:5) to give 110 mg of product as a yellowsolid (yield was 45%).

N-[6-(Pyridin-2-yloxy)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine

The mixture of2-[4-chloro-6-(pyridin-2-yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine(40 mg, 0.1 mmol) and ethane-1,2-diamine (2 mL) was heated with stirringin a 5 mL microwave process vial for 3 hours at 180° C. under microwaveirradiation. The solvent was removed under reduced pressure and theresidue was purified by preparative HPLC to give 7 mg of product as ayellow powder. MS obsd. (ESI⁺) [(M+H)⁺] 426. ¹H NMR (400 MHz, CD₃OD) δppm 8.12 (d, J=3.2 Hz, 1 H), 7.82-7.78 (m, 1 H), 7.66 (d, J=2.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1 H), 7.48 (d, J=6.8 Hz, 1 H), 7.23 (dd, J=5.2,2.4 Hz, 1 H), 7.16-7.08 (m, 4 H), 6.90 (d, J=8.4 Hz, 1 H), 6.04 (s, 1H), 4.83 (s, 2 H), 4.16 (brs, 2 H), 3.41 (t, J=6.2 Hz, 2 H), 3.05 (t,J=4.8 Hz, 2 H), 2.94 (t, J=6.2 Hz, 2 H), 1.96-1.91 (m, 2 H).

Example 1232-{4-[(2-Aminoethyl)amino]-6-chloroquinolin-2-yl}-N,N-dimethyl-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxamide

Methyl2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxylate

7-Bromo-2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-benzazepine(200 mg, 0.47 mmol), triethylamine (94 mg, 0.94 mmol) andtetrakis(triphenylphosphine)palladium(0) (49.2 mg, 0.047 mmol) wereadded into 10 mL of dry methanol. The resulting mixture was stirredunder reflux overnight under carbon monoxide. After cooled to roomtemperature, the reaction was diluted with ethyl acetate (30 mL), andthen washed with water. The organic fraction was dried over sodiumsulfate and concentrated in vacuo to give a residue which was purifiedby column chromatography on silica gel (ethyl acetate/petroleum ether,1:5) to give 156 mg of product (yield was 83%). MS obsd. (ESI⁺) [(M+H)⁺]401.

2-(4,6-Dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxylicacid

Methyl2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxylate(156 mg, 0.39 mmol) was added into the mixture of methanol (5 mL) andsodium hydroxide (5 M, 2 mL). The reaction mixture was stirred at roomtemperature overnight. After that, the reaction was diluted with 20 mLof water, acidified with 2 M of hydrochloric acid to pH 6 and dilutedwith ethyl acetate (30 mL). The organic layer was separated and washedwith water. The solvent was dried over sodium sulfate and concentratedin vacuo to give a residue which was purified by column chromatographyon silica gel to give 135 mg of product. MS obsd. (ESI⁺) [(M+H)⁺] 387.

2-(4,6-Dichloroquinolin-2-yl)-N,N-dimethyl-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxamide

The mixture of2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxylicacid (135 mg, 0.35 mmol), dimethylamine hydrochloride (34.2 mg, 0.42mmol), triethylamine (105 mg, 1.05 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (159 mg, 0.42 mmol) and 5 mL of dichloromethane wasstirred at room temperature overnight under nitrogen. The reaction wasdiluted with ethyl acetate (20 mL), washed with water and dried oversodium sulfate. The solvent was removed in vacuo and the residue waspurified by column chromatography to give 133 mg of product as a whitesolid. (yield was 92%). MS obsd. (ESI⁺) [(M+H)⁺] 414.

2-{4-[(2-Aminoethyl)amino]-6-chloroquinolin-2-yl}-N,N-dimethyl-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxamide

The mixture of2-(4,6-dichloroquinolin-2-yl)-N,N-dimethyl-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxamide(133 mg, 0.32 mmol) and ethane-1,2-diamine (2 mL) was heated withstirring in a 5 mL microwave process vial for 3 hours at 180° C. undermicrowave irradiation. The solvent was removed under reduced pressureand the residue was purified by preparative HPLC to give 11 mg ofproduct as a white solid. MS obsd. (ESI⁺) [(M+H)⁺] 438. ¹H NMR (400 MHz,CD₃OD) δ ppm 7.89 (s, 1 H), 7.60 (d, J=8.0 Hz, 1 H), 7.49 (d, J=8.8 Hz,1 H), 7.38 (m, 1 H), 7.22 (m, 2 H), 6.01 (s, 1 H), 4.80 (s, 2 H), 4.16(m, 2 H), 3.44 (t, J=6.4 Hz, 2 H), 3.11-2.97 (m, 10 H), 1.93 (m, 2 H).

Example 1242-{4-[(2-Aminoethyl)amino]quinolin-2-yl}-7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one

7-Bromo-2-(4-chloroquinolin-2-yl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one

To a solution of 2,4-dichloroquinoline (196 mg, 1.0 mmol) in dioxane (4mL) was added 7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one (161 mg,1.0 mmol), followed by tris(dibenzylideneacetone)dipalladium(0) (28 mg,0.03 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (65 mg, 0.11mmol), and potassium phosphate tribasic (212 mg, 1.0 mmol). Theresultant mixture was refilled with nitrogen and heated at 130° C.overnight. After cooled to room temperature, the mixture was dilutedwith acetonitrile (10 mL), filtered, and washed with acetonitrile. Thefiltrate was concentrated under reduced pressure to give a residue whichwas purified by column chromatography on silica gel (hexane/ethylacetate/ammonium hydroxide solution, 80:19:1) to give 165 mg of productas a white solid (yield was 42%). MS obsd. (ESI⁺) [(M+H)⁺] 401.

2-{4-[(2-Aminoethyl)amino]quinolin-2-yl}-7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one

To a solution of7-bromo-2-(4-chloroquinolin-2-yl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one(40 mg, 0.1 mmol) was added ethane-1,2-diamine (0.5 mL) in a microwavevessel, which was degassed and refilled with nitrogen. The resultantmixture was heated at 170° C. under microwave irradiation for 30minutes. After cooled to room temperature, the mixture was diluted withmethanol (10 mL) and concentrated under reduced pressure to give aresidue which was purified by preparative HPLC to afford 42 mg ofproduct as a solid (yield was 98%). MS obsd. (ESI⁺) [(M+H)⁺] 424. ¹H NMR(400 MHz, CD₃OD) δ ppm 7.99 (d, J=8.0 Hz, 1 H), 7.73 (d, J=8.0 Hz, 1 H),7.58 (m, 2 H), 7.47 (s, 2 H), 7.32 (td, J=1.2, 8.8 Hz, 1 H), 6.04 (s, 1H), 5.48 (s, 2 H), 3.42 (t, J=6.4 Hz, 2 H), 3.11 (t, J=7.6 Hz, 2 H),2.98 (t, J=6.0 Hz, 2 H), 2.86 (t, J=7.2 Hz, 2 H).

Example 1251-(2-{[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}ethyl)guanidinetrifluoroacetate

To a solution ofN-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine(200 mg, 0.6 mmol) and 3,5-dimethyl-1H-pyrazole-1-carboximidamidenitrate (122 mg, 0.6 mmol) in ethanol (15 mL) was refluxed by heatingfor overnight. After cooled to room temperature, the reaction mixturewas concentrated under reduced pressure, diluted with water (15 mL), andthen extracted with dichloromethane (50 mL×2). The dichloromethanefractions were combined and dried over sodium sulfate, and thenconcentrated under reduced pressure to give a residue which was purifiedby preparative HPLC to give 35.78 mg of product as a white solid. MSobsd. (ESI⁺) [(M+H)⁺] 375. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.07-8.04 (brs,1 H), 7.80-7.69 (m, 2 H), 7.51-7.41 (m, 2 H), 7.26-7.20 (m, 3 H), 6.00(s, 1 H), 4.98 (s, 2 H), 4.14 (s, 2 H), 3.71-3.67 (m, 2 H), 3.58-3.55(t, J=6.4 Hz, 2 H), 3.13-3.10 (m, 2 H), 2.01 (s, 2 H).

Example 126-1N-[(2-Amino-4,5-dihydro-1,3-oxazol-5-yl)methyl]-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-aminetrifluoroacetate

The mixture of1-amino-3-{[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-ol(690 mg, 1.9 mmol) and potassium acetate (490 mg, 5 mmol) in methanol (7mL) and water (1.75 mL) was stirred at 0° C. A cooled solution ofcyanogen bromide (212 mg, 2 mmol) in methanol (1 mL) was added to theabove mixture and the resultant mixture was stirred at room temperaturefor 4 hours. The reaction mixture was concentrated and diluted withethyl acetate (50 mL), and then washed with water (50 mL). The organicfraction was dried over sodium sulfate, and concentrated under reducedpressure to give a residue which was purified by preparative HPLC togive 73 mg of product as a white powder (yield was 10%). MS obsd. (ESI⁺)[(M+H)⁺] 388. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.06-8.04 (dd, J=8.4, 1.2Hz, 1 H), 7.80-7.78 (d, J=8.4 Hz, 1 H), 7.72 (m, 1 H), 7.50 (m, 1 H),7.42 (m, 1 H), 7.23 (m, 3 H), 6.11 (s, 1 H), 5.42 (m, 1 H), 4.99 (s, 2H), 4.11 (m, 3 H), 3.93 (d, J=5.6 Hz, 2 H), 3.77 (dd, J=9.6, 6.8 Hz, 1H), 3.09 (m, 2 H), 2.00 (d, J=5.6 Hz, 2 H).

Example 126-2N-[(2-Amino-4,5-dihydro-1,3-oxazol-5-yl)methyl]-6-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine

The title compound was prepared in analogy to Example 9-1 by using1-amino-3-{6-chloro-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-ol[It was prepared in Scheme 1 by using2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and1,3-diamino-propan-2-ol (commercial available) instead of7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and ethane-1,2-diaminerespectively.] instead of1-amino-3-{[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-ol.MS obsd. (ESI⁺) [(M+H)⁺] 422. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.17 (s, 1H), 7.82 (d, J=8.8 Hz, 1 H), 7.69 (m, 1 H), 7.52 (s, 1 H), 7.22 (m, 3H), 6.15 (s, 1 H), 5.42 (m, 1 H), 4.99 (s, 2 H), 4.11 (m, 3 H), 3.94 (d,J=5.6 Hz, 2 H), 3.77 (dd, J=9.6, 6.8 Hz, 1 H), 3.09 (m, 2 H), 2.00 (d,J=5.6 Hz, 2 H).

Example 127N-[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]glycinamide

2-Chloro-N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]acetamide

To the solution of2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine (500 mg,1.73 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.52 mL, 3.48mmol) followed by chloroacetyl chloride (0.21 mL, 2.64 mmol) at roomtemperature. The resulting solution was heated with stirring at 70° C.for 2 hours under nitrogen. After cooled to room temperature, thereaction was diluted with ethyl acetate (50 mL), and then washed withwater (50 mL×3). The organic phase was dried over sodium sulfate andconcentrated under reduced pressure to give a residue which was purifiedby column chromatography on silica gel (ethyl acetate/petroleum ether,1:4) to give 140 mg of product as an off-white solid (yield was 22.1%).MS obsd. (ESI⁺) [(M+H)⁺] 366.

2-Azido-N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]acetamide

To a solution of2-chloro-N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]acetamide(70 mg, 0.19 mmol) in acetonitrile (2 mL) was added sodium azide (62 mg,0.95 mmol). The resulting mixture was stirred at room temperature for 6hours. The reaction was diluted with ethyl acetate (20 mL), and thenwashed with water (10 mL). The ethyl acetate fraction was dried oversodium sulfate, and then concentrated under reduced pressure to give aresidue which was purified by column chromatography on silica gel (ethylacetate/petroleum ether, 1:4) to give 65 mg of product as a white powder(yield was 91.8%). MS obsd. (ESI⁺) [(M+H)⁺] 373.

N-[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]glycinamide

To a solution of2-azido-N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]acetamide(65 mg, 0.17 mmol) in methanol was added palladium (10% on carbon, 7mg). After being stirred at room temperature overnight under a hydrogenatmosphere, the resulting mixture was filtered. The filtrate wasconcentrated in vacuo and the residue was purified by preparative HPLCto afford 30 mg of product as a white powder (yield was 60.5%). MS obsd.(ESI⁺) [(M+H)⁺] 347. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (s, 1 H), 7.78(d, J=8.0 Hz, 1 H), 7.55-7.49 (m, 3 H), 7.23-7.20 (m, 1 H), 7.15-7.08(m, 3 H), 4.79 (s, 2 H), 4.13 (brs, 2 H), 3.45 (brs, 2 H), 3.04 (brs, 2H), 1.79 (brs, 2 H).

Example 1283-[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propan-1-amine

Methyl(2E)-3-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]prop-2-enoate

The mixture of2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (1.5 g,4.86 mmol), acrylic acid methyl ester (0.88 ml, 9.7 mmol), triethylamine(6 mL) and N,N-dimethylformamide (6 mL),bis(tri-tert-butylphosphine)palladium(0) (124 mg, 0.243 mmol) was heatedwith stirring in a 20 mL of microwave process vial for 30 minutes at100° C. under argon. The reaction mixture was poured into water (30 mL)and extracted with ethyl acetate (20 mL×3). The organic layers werecombined, washed with brine, dried over sodium sulfate and concentratedin vacuo to give a residue which was purified by flash column to afford1.41 g of product as a white solid (yield was 81%). MS obsd. (ESI⁺)[(M+H)⁺] 359.

Methyl3-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propanoate

To a solution of methyl(2E)-3-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]prop-2-enoate(1.4 g, 3.91 mmol) in 30 mL of methanol was added 10% palladium oncarbon (70 mg). After being vigorously stirred under hydrogen (balloon)for 3 hours, the reaction was filtered and the filtrate was concentratedin vacuo to give 1.4 g of product as a white solid (yield was 98%). MSobsd. (ESI⁺) [(M+H)⁺] 361.

3-[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propanoicacid

To a solution of methyl3-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propanoate(1.4 g, 3.89 mmol) in methanol (10 mL) was added an aqueous solution ofsodium hydroxide (4 N, 16 mL) and the resulting mixture was stirred atroom temperature for 4 hours. The reaction was acidified to pH 4 with 5N hydrochloric acid, and then extracted with ethyl acetate (10 mL×3).The organic layer was dried over sodium sulfate and concentrated invacuo to give a residue which was purified by flash columnchromatography to afford 1.1 g of product as a white solid (yield was82%). MS obsd. (ESI⁺) [(M+H)⁺] 347.

3-[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propanamide

To a solution of3-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propanoicacid (300 mg, 0.867 mmol) in dichloromethane (10 mL) was added oxalylchloride (0.123 mL, 1.3 mmol) and one drop of N,N-dimethylformamide at0° C. The resulting mixture was warmed to room temperature and stirredfor further 2 hours. The solvent was removed under reduced pressure andthe residue was dissolved in dichloromethane (5 mL), to which atetrahydrofuran solution of ammonia (4 N, 5 mL) was added at 0° C.,followed by stirring at room temperature overnight. The reaction wasconcentrated in vacuo to dryness and purified by flash column to afford50 mg of product as a white solid. It was used in next step withoutfurther purification. MS obsd. (ESI⁺) [(M+H)⁺] 346.

3-[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propan-1-amine

To the mixture of3-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propanamide(50 mg, 0.145 mmol) in tetrahydrofuran (5 mL) was added atetrahydrofuran solution of borane (1.5 mL, 1.5 mmol) at 0° C., followedby stirring at 70° C. for 4 hours. After being quenched with methanol (5mL) at 0° C., the resulting mixture was concentrated in vacuo to give aresidue which was purified by flash column (ethyl acetate/hexane, 3:7)to afford 10 mg of product as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]332. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (d, J=7.2 Hz, 1 H), 7.57-7.52(m, 2 H), 7.47-7.43 (m, 1 H), 7.18-7.04 (m, 5 H), 5.24 (brs, 2 H), 4.85(s, 2 H), 4.14 (brs, 2 H), 3.03 (brs, 2 H), 2.93 (t, J=7.2 Hz, 2 H),1.89-1.82 (m, 4 H).

Example 129[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]methanol

Methyl2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-carboxylate

The mixture of 2-chloroquinoline-4-carboxylic acid methyl ester (3 g,13.5 mmol), 2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride (3 g, 16.3mmol), potassium carbonate (4.5 g, 32.6 mmol), tetrabutylammonium iodide(300 mg) and toluene (60 mL) was heated with stirring at 110° C. for 5days. The solvent was removed under reduced pressure to give a residuewhich was purified by column chromatography on silica gel (ethylacetate/petroleum ether, 1:4) to give 1.97 g of product as a yellowsolid. MS obsd. (ESI⁺) [(M+H)⁺] 333.

[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]methanol

To the mixture of methyl2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-carboxylate (30mg, 0.087 mmol) in tetrahydrofuran (2 mL) was added a tetrahydrofuransolution of borane (1.5 mL, 1.5 mmol) at 0° C. After being stirred at70° C. for 4 hours, the mixture was quenched with methanol (5 mL) at 0°C. The solvent was removed in vacuo to give a residue which was purifiedby flash column (ethyl acetate/hexane, 3:7) to afford 16 mg of productas a white solid. MS obsd. (ESI⁺) [(M+H)⁺] 305. ¹H NMR (400 MHz,DMSO-d6) δ ppm 7.70 (d, J=8.0 Hz, 1 H), 7.56-7.44 (m, 3 H), 7.25 (s, 1H), 7.16-7.07 (m, 4 H), 5.44 (t, J=4.2 Hz, 1 H), 4.86 (s, 2 H), 4.85 (s,2 H), 4.18 (brs, 2 H), 3.04 (brs, 2 H), 1.80 (brs, 2 H).

Example 130-12-(6-Chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine

2-[6-Chloro-4-(prop-2-en-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine

The mixture of2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (200mg, 0.58 mmol), 2-allyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.164mL, 0.87 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.058mmol), potassium carbonate (241 mg, 1.74 mmol), 1,2-dimethoxyethane (3mL) and water (1 mL) was heated with stirring in a 10 mL of microwaveprocess vial for 3 hours at 120° C. under microwave irradiation. Theresulting mixture was diluted with ethyl acetate (20 mL), and thenwashed with water (20 mL). The ethyl acetate fraction was dried oversodium sulfate, and then concentrated under reduced pressure to give aresidue which was separated by column chromatography on silica gel(ethyl acetate/petroleum ether, 0.1:5) to afford2-[6-chloro-4-(prop-2-en-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine(20 mg) and2-(6-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (50 mg).

2-[6-chloro-4-(prop-2-en-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine

MS obsd. (ESI⁺) [(M+H)⁺] 349.

2-(6-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine

MS obsd. (ESI⁺) [(M+H)⁺] 309. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.93 (d,J=9.2 Hz, 1 H), 7.72 (brs, 1 H), 7.56-7.51 (m, 2 H), 7.47-7.44 (m, 1 H),7.29 (d, J=9.6 Hz, 1 H), 7.14-7.08 (m, 3 H), 4.85 (brs, 2 H), 4.14 (brs,2 H), 3.03 (brs, 2 H), 1.78 (brs, 2 H).

Example 130-23-[6-Chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propane-1,2-diol

To a solution of2-[6-chloro-4-(prop-2-en-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine(20 mg, 0.057 mmol) in acetone (2 mL) and water (1 mL) was addedN-methyl morpholine-N-oxide (50% in water, 15.5 mg, 0.057 mmol) followedby osmium tetroxide (0.14 mg, 0.0005 mmol). The resulting mixture wasstirred at room temperature overnight. The solvent was removed underreduced pressure and the residue was purified by column chromatographyon silica gel (ethyl acetate/petroleum ether, 3:2) to give 14 mg ofproduct as colorless oil. MS obsd. (ESI⁺) [(M+H)⁺] 383. ¹H NMR (400 MHz,CD₃OD) δ ppm 7.82 (d, J=2.0 Hz, 1 H), 7.58 (d, J=8.8 Hz, 1 H), 7.50 (d,J=6.8 Hz, 1 H), 7.40 (dd, J=9.2, 2.4 Hz, 1 H), 7.14-7.08 (m, 4 H), 4.84(brs, 2 H), 4.21 (brs, 1 H), 4.10 (brs, 1 H), 3.91-3.88 (m, 1 H),3.58-3.55 (m, 2 H), 3.21 (dd, J=14.0, 4.4 Hz, 1 H), 3.04 (d, J=6.4 Hz, 2H), 2.87 (dd, J=14.0, 8.4 Hz, 1 H), 1.91-1.86 (m, 2 H).

Example 131(4S)-4-{2-[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethyl}-4,5-dihydro-1,3-oxazol-2-amine

tert-Butyl(4S)-2,2-dimethyl-4-{(E)-2-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethenyl}-1,3-oxazolidine-3-carboxylate

The mixture of2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (310 mg,1.0 mmol), (S)-2,2-dimethyl-4-vinyl-oxazolidine-3-carboxylic acidtert-butyl ester (273 mg, 1.2 mmol),bis(tri-tert-butylphosphine)palladium(0) (51 mg, 0.1 mmol), methyldicyclohexylamine (293 mg, 1.5 mmol) and N,N-dimethylformamide (6 mL)was heated with stirring in a 20 mL microwave process vial for 2.5 hoursat 120° C. under microwave irradiation. The reaction mixture was dilutedwith ethyl acetate and washed with brine. The organic layer was driedover sodium sulfate, and then concentrated under reduced pressure togive a residue which was purified by flash column to give 380 mg ofproduct as a white solid (yield was 76%). MS obsd. (ESI⁺) [(M+H)⁺] 500.

tert-Butyl(4S)-2,2-dimethyl-4-{2-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethyl}-1,3-oxazolidine-3-carboxylate

The mixture of tert-butyl(4S)-2,2-dimethyl-4-{(E)-2-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethenyl}-1,3-oxazolidine-3-carboxylate(380 mg, 0.76 mmol), palladium hydroxide (20% on carbon, 50 mg) andethanol (15 mL) was stirred at room temperature for 4 hours underhydrogen. The solid was filtered by a pad of silica gel and the filtratewas concentrated in vacuo to give 340 mg of product as a white solid(yield was 89%). MS obsd. (ESI⁺) [(M+H)⁺] 502.

(2S)-2-Amino-4-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]butan-1-ol

To the solution of tert-butyl(4S)-2,2-dimethyl-4-{2-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethyl}-1,3-oxazolidine-3-carboxylate(340 mg, 0.68 mmol) in ethyl acetate was introduced hydrochloric acidgas for 30 minutes. After being stirred at room temperature overnight,the reaction was poured into ice-water then neutralized with saturatedsodium carbonate. The organic layer was separated, dried over sodiumsulfate, and then concentrated in vacuo to give the product. It was usedin next step without further purification. MS obsd. (ESI⁺) [(M+H)⁺] 362.

(4S)-4-{2-[2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethyl}-4,5-dihydro-1,3-oxazol-2-amine

To the stirred mixture of(2S)-2-amino-4-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]butan-1-ol(110 mg, 0.3 mmol), potassium acetate (90 mg, 0.91 mmol), methanol (8mL) and water (2 mL) was added a solution of cyanogen bromide (32.3 mg,0.3 mmol) in cold methanol (2 mL) at 0° C. After the addition, theresulting mixture was stirred at room temperature for 24 hours. Thesolvent was removed under reduced pressure to give a residue which waspurified by preparative HPLC to give 40 mg of product as a white solid(yield was 34.5%). MS obsd. (ESI⁺) [(M+H)⁺] 387. ¹H NMR (400 MHz,DMSO-d6) δ ppm 7.77 (d, J=7.2 Hz, 1 H), 7.56-7.43 (m, 3 H), 7.17-7.04(m, 4 H), 5.91 (brs, 1 H), 4.84 (s, 2 H), 4.21 (t, J=8.0 Hz, 2 H), 4.13(brs, 2 H), 3.87 (t, J=7.2 Hz, 1 H), 3.77 (t, J=7.2 Hz, 1 H), 3.01 (brs,2 H), 2.94-2.89 (m, 1 H), 1.78 (brs, 2 H), 1.72-1.67 (m, 2 H).

Example 132N-(2-Aminoethyl)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-sulfonamidetrifluoroacetate

2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-thiol

A mixture of2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (2 g, 6.47mmol) and sodium thiomethoxide (2.4 g, 34 mmol) in dryN,N-dimethylformamide (20 mL) was heated with stirring overnight underreflux. The reaction mixture was cooled to 50° C. and the volatilecomponents were evaporated under reduced pressure to give a residuewhich was dissolved in 30 mL of chilled water and carefully acidifiedwith 20% hydrochloride aid to pH 4-5 under argon. The resultant solutionwas extracted with chilled dichloromethane (30 mL×3). Thedichloromethane fractions were combined and washed with chilled brine(30 mL×2) and then concentrated under reduced pressure at roomtemperature to give the crude product. It was used in next step withoutfurther purification.

2-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-sulfonyl chloride

Gaseous chlorine was passed through a well stirred solution of2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-thiol (2 g, 6.5mmol) in concentrated hydrochloric acid (17 mL) at −10° C. at such arate that temperature was maintained between −5 and −10° C. The passageof chlorine was discontinued after 30 minutes. The mixture was pouredinto ice (30 g) followed by addition of sodium bicarbonate (4 g) insmall portions. The resultant mixture was extracted with chilleddichloromethane (30 mL×3). The dichloromethane fractions were combinedand washed with chilled water (20 mL), and then dried over sodiumsulfate, filtered and the filtrate was used in next step without furtherpurification.

N-(2-Aminoethyl)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-sulfonamidetrifluoroacetate

To a solution of ethane-1,2-diamine (500 mg, 8.3 mmol) indichloromethane (20 mL) was added a cold triethylamine (5 drops) in anice-water bath, followed by the addition of the solution of2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-sulfonyl chloride(400 mg, 0.9 mmol) in dichloromethane (20 mL) prepared above slowly.After being stirred overnight, the solvent was removed under reducedpressure, and the residue was purified by preparative HPLC to give 43.6mg of product (yield was 12.2%). MS obsd. (ESI⁺) [(M+H)⁺] 397. ¹H NMR(400 MHz, CD₃OD) δ ppm 8.37-8.35 (m, 1 H), 7.88-7.82 (m, 2 H), 7.71 (m,1 H), 7.48-7.42 (m, 2 H), 7.18-7.17 (m, 3 H), 5.02 (s, 2 H), 4.23 (s, 2H), 3.09-3.03 (m, 6 H), 1.98 (s, 2 H).

Example 133-14-{4-[(2-Aminoethyl)amino]-6-methylquinolin-2-yl}-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one

4-(4-Chloro-6-methylquinolin-2-yl)-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one

The mixture of 2,4-dichloro-6-methyl-quinoline (422 mg, 2 mmol),1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one (298 mg, 2 mmol) andn-butyl alcohol (15 mL) was heated with stirring in a 20 mL microwaveprocess vial for 3 hours at 160° C. under microwave irradiation. Aftercooling, the solvent was removed in vacuo and the residue was purifiedby column chromatography on silica gel (methanol/dichloromethane, 1:20)to give the product. MS obsd. (ESI⁺) [(M+H)⁺] 338.

4-{4-[(2-Aminoethyl)amino]-6-methylquinolin-2-yl}-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one

The mixture of4-(4-chloro-6-methylquinolin-2-yl)-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one(60 mg, 1 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), (8.2 mg,0.01 mmol), bis(diphenylphosphino)ferrocene (6 mg, 0.01 mmol) and sodiumtert-butoxide (20 mg, 0.2 mmol) and 1,4-dioxane (2 mL) was heated withstirring in a 10 mL microwave process vial for 1 hour at 120° C. undermicrowave irradiation. After cooling, the mixture was filtered andwashed with ethyl acetate. The filtrate was washed with brine, driedover sodium sulfate, and concentrated in vacuo to give a residue whichwas purified by preparative HPLC to afford the product as a solid. MSobsd. (ESI⁺) [(M+H)⁺] 362. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.64 (s, 1 H),7.44-7.40 (m, 2 H), 7.28 (dd, J=1.6, 8.4 Hz, 1 H), 7.18 (dd, J=1.6, 8.0Hz, 1 H), 7.09 (dd, J=0.8, 8.0 Hz, 1 H), 6.98 (dd, J=0.8, 8.0 Hz, 1 H),6.00 (s, 1 H), 4.87 (s, 2 H), 4.72 (s, 2 H), 3.40 (t, J=6.4 Hz, 2 H),2.95 (t, J=6.4 Hz, 2 H), 2.40 (s, 3 H).

Example 133-2N-[6-Methyl-2-(1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl)quinolin-4-yl]ethane-1,2-diamine

The title compound was prepared in analogy to Example 16-1 by using2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (commercial available) insteadof 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one. MS obsd. (ESI⁺)[(M+H)+] 348. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.90 (s, 1 H), 7.67 (d,J=8.4 Hz, 1 H), 7.58 (d, J=8.4 Hz, 1 H), 7.42 (d, J=7.2 Hz, 1 H), 7.12(t, J=8.0 Hz, 1 H), 6.88 (t, J=7.2 Hz, 1 H), 6.82 (d, J=8.0 Hz, 1 H),5.95 (s, 1 H), 4.87 (s, 2 H), 4.00 (t, J=4.8 Hz, 2 H), 3.72 (t, J=6.0Hz, 2 H), 3.46 (t, J=4.8 Hz, 2 H), 3.18 (t, J=6.0 Hz, 2 H), 2.49 (s, 3H).

Example 134N-[2-(2,3-Dihydro-1,4-benzoxazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine

Methyl (2-cyanophenoxy)acetate

To the mixture of 2-hydroxybenzonitrile (40 g, 0.34 mol) and potassiumcarbonate (51.6 g, 0.374 mol) in 850 mL of acetone was added methylbromoacetate (51.7 g, 0.34 mol) slowly at room temperature. After beingstirred at room temperature overnight, the solid was filtered off. Thefiltrate was concentrated under reduced pressure and the residue wasdissolved in ethyl acetate. The organic layer was washed with water thenbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure to give a residue which was recrystallized in methanolto give 40 g of product as a white solid.

4,5-Dihydro-1,4-benzoxazepin-3(2H)-one

The methanol solution of methyl (2-cyanophenoxy)acetate (40 g, 0.209mol) was added to the mixture of Raney Ni (80 g) in 500 mL of methanol.The reaction mixture was stirred at room temperature overnight underhydrogen atmosphere. Raney Ni was removed by filtration, and thefiltrated was concentrated under reduced pressure to give a residuewhich was purified by column chromatography on silica gel(methanol/dichloromethane, 1:50) to give 23 g of product. MS obsd.(ESI⁺) [(M+H)⁺] 164.

2,3,4,5-Tetrahydro-1,4-benzoxazepine

To the suspension of lithium aluminium hydride (15.2 g, 0.4 mol) in 600mL of ether was added a solution of4,5-dihydro-1,4-benzoxazepin-3(2H)-one (16.3 g, 0.1 mol) in 60 mL oftetrahydrofuran at room temperature. After being heated with stirringunder reflux overnight, water was added dropwise to quench the reactionat 0° C., The resulting mixture was diluted with ethyl acetate, and thenfiltered by a pad of celite. The filtrate was concentrated under reducedpressure, followed by the addition of hydrochloric acid ethyl acetatesolution. The hydrochloride was collected by filtration, washed withethyl acetate then ether, and then dried in vacuo to give 13.5 g ofproduct. MS obsd. (ESI⁺) [(M+H)⁺] 150.

4-(4-Chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine

The mixture of 2,4-dichloroquinoline (198 mg, 0.1 mmol),2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (186 mg, 0.1 mmol),diisopropylethylamine (0.4 mL) and 5 mL of N-methyl-2-pyrrolidone washeated with stirring at 100° C. overnight. The mixture was cooled toroom temperature, diluted with brine, and extracted with ethyl acetate(30 mL×3). The organic layers were combined and washed with brine. Thesolvent was dried over sodium sulfate and removed under reduced pressureto give a residue which was purified by column chromatography on silicagel to give 119 mg of product as a white solid. MS obsd. (ESI⁺) [(M+H)⁺]311.

N-[2-(2,3-Dihydro-1,4-benzoxazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine

The mixture of4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg,0.32 mmol) and 1.6 mL of ethane-1,2-diamine was heated with stirring ina 5 mL microwave process vial for 3 hours at 150° C. under microwaveirradiation. The mixture was concentrate in vacuo to give a residuewhich was purified by preparative HPLC to give 31 mg of product as awhite solid. MS obsd. (ESI⁺) [(M+H)⁺] 335. ¹H NMR (400 MHz, CD₃OD) δ ppm8.61 (s, 1 H), 7.90 (d, J=7.6 Hz, 1 H), 7.60-7.51 (m, 3 H), 7.23 (brs, 2H), 7.09-6.98 (m, 2 H), 6.05 (s, 1 H), 4.89 (s, 2 H), 4.27 (s, 2 H),4.25 (s, 2 H), 3.61 (s, 2 H), 3.15 (s, 2 H).

Example 135-1N-[(1-Aminocyclopropyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine

tert-Butyl(1-{[(2-chloro-6-methylquinazolin-4-yl)amino]methyl}cyclopropyl)carbamate

To a solution of tert-butyl [1-(aminomethyl)cyclopropyl]carbamate (0.92g, 4.9 mmol) in tetrahydrofuran (50 mL) was added triethylamine (1.3 mL,9.4 mmol) followed by 2,4-dichloro-6-methylquinazoline (1.0 g, 4.7 mmol)in portions at room temperature. After being stirred at room temperatureovernight, the resultant mixture was concentrated in vacuo to remove 20mL of solvent and then stirred vigorously with water (200 mL). Theformed solid was collected by filtration and washed with water andether, then dried in vacuo to afford 1.5 g of the product as a whitepowder.

tert-Butyl[({2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]amino}methyl)cyclopropyl]carbamate

A mixture of tert-butyl(1-{[(2-chloro-6-methylquinazolin-4-yl)amino]methyl}cyclopropyl)carbamate(1.5 g, 4.1 mmol), 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide(0.82 g, 4.1 mmol) and catalystic amount of ammonium chloride in ethanol(40 mL) was heated with stirring at 70° C. overnight. The reactionmixture was then cooled to room temperature. The formed solid wascollected by filtration, then washed with ethanol and dried in vacuo.The crude solid (1.5 g) was suspended in dichloromethane (50 mL) andbasified with 1 N of sodium hydroxide. The organic phase was separatedand used for the next step directly.

(1-Amino-cyclopropylmethyl)-[2-(5,5-dioxo-5,6,7,9-tetrahydro-5lambda*6*-thia-8-aza-benzocyclohepten-8-yl)-6-methyl-quinazolin-4-yl]-amine

To the solution obtained above was added trifluoroacetic acid (10 mL)and the mixture was stirred at room temperature for 30 minutes. Thereaction was quenched with saturated aqueous solution of sodiumcarbonate. The organic layer was separated and dried over sodiumsulfate, filtrated and concentrated in vacuo. The residue was stirredwith methanol. The produced white solid was collected by filtration anddried in vacuo to afford 400 mg of the product as a white powder. MSobsd. (ESI⁺) [(M+H)⁺] 424, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.95-7.85 (m,2 H), 7.74 (br. s., 2 H), 7.62 (t, J=7.00 Hz, 1 H), 7.47 (t, J=8.30 Hz,1 H), 7.35 (dd, J=8.53, 1.51 Hz, 1 H), 7.23 (d, J=7.78 Hz, 1 H), 5.07(br. s., 2 H), 4.44 (br. s., 2 H), 3.32 (s, 2 H), 2.35 (s, 3 H), 2.04(s, 2 H), 0.52 (d, J=30.62 Hz, 4 H).

Example 135-22-(1,1-Dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinazolin-4-amine

The title compound was prepared in analogy to Example 135-1 in Scheme 70by using 2,4-dichloro-6-methylquinazoline, tert-butyl3-aminopyrrolidine-1-carboxylate, 2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide and trifluoroacetic acid instead of2,4-dichloro-6-methylquinazoline, tert-butyl[1-(aminomethyl)cyclopropyl]carbamate,2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and trifluoroaceticacid. MS obsd. (ESI⁺) [(M+H)⁺] 424, ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.92-7.82 (m, 2 H), 7.78 (br. s., 1 H), 7.69-7.56 (m, 2 H), 7.48 (t,J=7.53 Hz, 1 H), 7.34 (dd, J=8.53, 1.25 Hz, 1 H), 7.22 (d, J=6.78 Hz, 1H), 5.08 (br. s., 2 H), 4.47 (br. s., 2 H), 3.48-2.54 (m, 7 H), 2.33 (s,3 H), 2.25-2.00 (m, 1 H), 1.81-1.68 (m, 1 H).

Example 136

Viral cytopathic effect (CPE) assay: To measure anti-RSV activity ofcompounds, 96-well plates are seeded with 6×10³ cells per well inDulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovineserum (FBS). Cells are infected the next day with sufficient RSV Longstrain (ATCC) to produce an approximately 80-90% cytopathic effect after6 days, in the presence of serial half-log diluted compound in a totalvolume of 200 μL per well. The viability of cells is assessed after 6days using Cell Counting kit-8 (Dojindo Molecular Technologies). Theabsorbance at 450 nm and referenced at 630 nm is measured to determine50% effective concentration (EC₅₀).

The compounds of the present invention were tested for their anti-RSVactivity, and the activation as described herein. The Examples weretested in the above assay and found to have EC₅₀ of about 0.0001 μM toabout 10 μM. Particular compound of formula (I) were found to have EC₅₀of about 0.0001 μM to about 1 μM. Further particular compound of formula(I) were found to have EC₅₀ of about 0.0001 μM to about 0.1 μM.

Results of CPE assays are given in Table 1.

TABLE 1 EC50 (μM, Example Long Strain)  1-1 0.002  1-2 0.007  1-3 0.072 1-4 0.004  1-5 0.004  1-6 0.022  1-7 0.022  2-1 0.024  2-2 0.002  2-32.805  2-4 0.081  2-5 0.006  2-6 0.021  2-7 0.234  2-8 0.055  2-9 0.007 2-10 0.005  2-11 0.008  3-1 0.006  3-2 3.051  3-3 3.552  3-4 0.006  3-50.002  3-6 0.058  3-7 0.009  3-8 0.002  3-9 0.248  3-10 0.053  3-110.054  3-12 1.654  3-13 0.099  3-14 0.017  3-15 0.482  3-16 0.075  3-175.053  3-18 0.024  3-19 0.009  3-20 0.507  3-21 0.006  3-22 0.032  3-230.002  3-24 0.021  3-25 0.022  3-26 0.876  3-27 1.394  3-28 0.149  3-290.022  3-30 7.81  3-31 0.014  3-32 0.037  3-33 0.426  3-34 0.085  3-350.013  3-36 0.092  3-37 0.017  3-38 0.0439  3-39 0.030  3-40 0.022  3-410.071  3-42 0.007  3-43 2.394  3-44 0.012  3-45 5.229  3-46 0.053  3-470.101  3-48 0.023  3-49 0.099  3-50 0.0004  3-51 0.004  3-52 0.005  3-530.261  3-54 0.114  3-55 0.027  3-56 0.716  3-57 7.534  3-58 0.184  3-591.083  3-60 0.617  3-61 0.118  3-62 0.589  3-63 9.899  3-64 0.874  3-650.002  4-1 0.269  4-2 0.098  4-3 0.026  4-4 0.208  4-5 5.258  5-1 9.197 5-2 0.211  5-3 0.015  5-4 0.326  5-5 0.014  5-6 2.062  5-7 0.941  5-80.022  5-9 0.018  5-10 0.397  5-11 0.526  5-12 6.249  6-1 0.025  6-20.908  7 1.418  8-1 5.513  8-2 0.817  8-3 0.9  8-4 0.064  8-5 0.074  8-63.767  8-7 0.322  9-1 2.35  9-2 4.77  9-3 0.001  9-4 8.874  9-5 0.179 9-6 0.275  9-7 0.002  9-8 3.478  9-9 0.157  9-10 0.037  9-11 0.953 9-12 2.663  9-13 0.701  9-14 0.025  9-15 0.012  9-16 0.005  9-17 0.025 9-18 0.01  9-19 0.0007  9-20 0.760  9-21 0.021  9-22 0.872  9-23 3.022 9-24 0.024  9-25 4.084  9-26 7.204  9-27 0.797  9-28 0.003  9-29 0.024 9-30 8.591  9-31 2.427  9-32 0.063  9-33 0.057  9-34 0.024 10 0.00311-1 0.069 11-2 7.022 11-3 0.922 11-4 0.004 12-1 0.536 12-2 0.315 12-36.256 12-4 0.764 12-5 0.448 12-6 9.214 12-7 0.226 13 0.026 14-1 2.19414-2 8.792 15-1 7.892 15-2 7.994 15-3 2.697 15-4 0.257 15-5 0.740 16-12.567 16-2 9.642 17-1 5.538 17-2 0.616 17-3 2.17 17-4 0.071 17-5 1.50417-6 0.086 17-7 0.642 17-8 0.021 18-1 0.003 18-2 0.024 18-3 0.014 18-40.061 18-5 0.057 18-6 0.061 18-7 0.023 18-8 0.0007 18-9 0.005  18-100.011  18-11 0.619 19-1 0.043 19-2 0.011 19-3 0.006 19-4 0.02 19-5 3.07319-6 0.054 19-7 6.856 19-8 2.749 20-1 0.073 20-2 0.31 20-3 0.093 21-10.023 21-2 0.161 21-3 0.015 21-4 0.004 21-5 0.007 22 0.036 23 5.185 240.016 25 0.002 26-1 0.005 26-2 0.179 27 2.393 28-1 0.007 28-2 0.007 28-30.001 28-4 0.001 28-5 0.003 29 0.042 30-1 0.317 30-2 0.218 31 0.702 32-10.019 32-2 2.454 32-3 1.991 32-4 0.272 32-5 2.58 33-1 0.044 33-2 0.62734 2.086 35 2.791 36-1 0.073 36-2 1.474 36-3 2.153 36-4 0.138 36-5 0.02636-6 0.264 37-1 0.005 37-2 0.043 38-1 0.01 38-2 0.302 38-3 0.074 38-40.064 38-5 6.652 39 0.092 40-1 0.039 40-2 4.655 40-3 0.917 40-4 2.646 412.629 42-1 8.947 42-2 0.037 43 0.017 44-1 0.084 44-2 1.547 45-1 0.02145-2 0.253 45-3 0.031 46 0.682 47-1 7.881 47-2 5.822 47-3 5.692 47-40.993 47-5 0.835 47-6 2.312 47-7 3.4107 47-8 0.432 47-9 0.192 48 0.00949 0.721 50-1 0.931 50-2 2.423 51 0.056 52 0.419 53 0.094 54 4.798 55-10.007 55-2 0.202 55-3 0.006 56-1 0.002 56-2 0.023 56-3 0.004 56-4 0.02756-5 0.022 56-6 0.002 57-1 0.067 57-2 0.018 57-3 0.023 57-4 0.239 57-50.027 57-6 0.037 57-7 0.081 58 2.772 59 0.746 60 0.018 61-1 0.005 61-20.097 62-1 0.0003 62-2 0.0017 62-3 0.0013 62-4 0.019 62-5 0.017 62-60.006 62-7 0.186 63-1 3.133 63-2 2.021 63-3 0.007 63-4 0.797 64 0.035 650.322 66 0.002 67 0.585 68 2.012 69-1 0.007 69-2 0.007 70 0.071 71 0.00572 0.002 73 6.978 74 1.936 75 0.002 76 0.006 77 8.78 78-1 0.016 78-20.25 79 2.791 80 5.479 81 0.353 82 0.014 83 0.662 84 2.965 85 0.008 862.222 87-1 0.096 87-2 9.31 88 0.007 89 0.007 90 0.005 91 0.004 92-10.009 92-2 0.019 93-1 0.005 93-2 0.009 94 6.527 95 3.039 96 2.833 970.177 98-1 0.778 98-2 3.163 99 2.999 100  9.191 101  8.579 102  9.76103  0.202 104  0.89 105  1.084 106  0.002 107  0.001 108-1  0.488108-2  2.474 109-1  0.00088 109-2  0.0015 110-1  0.017 110-2  2.607110-3  0.161 110-4  0.06 110-5  1.655 110-6  4.278 110-7  1.178 110-8 0.081 110-9  1.367 110-10 0.099 110-11 6.753 110-12 0.072 110-13 3.679110-14 0.648 110-15 0.004 111-1  2.007 111-2  1.345 111-3  0.0768 111-4 0.066 111-5  1.64 111-6  0.062 111-7  0.873 111-8  0.283 111-9  0.047111-10 0.107 111-11 0.588 112-1  3.739 112-2  0.092 113  0.733 114-1 0.007 114-2  0.975 114-3  0.004 114-4  0.186 115  0.01 116-1  0.005116-2  0.309 117  5.97 118-1  1.975 118-2  0.048 118-3  0.063 118-4 0.104 118-5  0.178 118-6  0.173 118-7  0.166 118-8  0.223 118-9  0.202118-10 0.289 118-11 0.323 118-12 0.448 118-13 0.463 118-14 0.616 118-150.626 118-16 0.695 118-17 0.806 118-18 0.973 118-19 1.236 118-20 1.129118-21 1.382 118-22 2.227 118-23 2.641 118-24 6.451 118-25 7.623 118-267.754 119  6.656 120-1  2.193 120-2  1.785 121  1.103 122  3.125 123 3.144 124  6.102 125  2.521 126-1  0.790 126-2  0.638 127  6.249 128 7.174 129  7.875 130-1  6.836 130-2  7.269 131  2.523 132  7.814 133-1 0.31 133-2  0.186 134  0.25 135-1  0.006 135-2  0.018

Example A

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of tablets of the followingcomposition:

Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mgCorn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example B

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of capsules of the followingcomposition:

Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

The invention claimed is:
 1. A compound of formula (I)

Wherein R¹ is hydrogen, halogen, or C₁₋₆alkyl; R² is hydrogen, halogen,or C₁₋₆alkyl; R³ is hydrogen, halogen, or C₁₋₆alkyl; R⁴ is hydrogen, orC₁₋₆alkyl; R⁵ is hydrogen, or halogen; R⁶ is hydrogen, halogen, hydroxy,C₁₋₆alkoxy, carboxy, morpholinyl, or 4-C₀₋₆alkylpiperazin-1-yl; R⁷ ishydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylaminocarbonyl,diC₁₋₆alkylaminocarbonyl, C₁₋₆alkylsulfonyl, phenoxy, orhydroxy(CH₂)₂₋₆—O—; R⁸ is hydrogen, halogen, or C₁₋₆alkoxy; R⁹ ishydrogen, C₁₋₆alkyl, or ═O; R¹⁰ is hydrogen, or ═O, provided that R⁹ andR¹⁰ are not ═O simultaneously; A is nitrogen, or —C—R¹¹, wherein R¹¹ ishydrogen, halogen, C₁₋₆alkyl, cycloalkyl, C₁₋₆alkoxy, trifluoromethyl,trifluoromethoxy, pyridinyloxy, C₁₋₆alkoxy(CH₂)₁₋₆—O—, difluoromethoxy,cyano, nitro, amino, vinyl, acetylenyl, aminocarbonyl,hydroxy(CH₂)₂₋₆—O—, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl,hydroxy(CH₂)₁₋₆, deuteratedC₁₋₆alkyl, carboxyl, C₁₋₆alkoxycarbonyl,hydroxy, difluoromethyl, —CH(hydroxy) C₁₋₆alkyl, or C₁₋₆alkylsulfanyl; Xis —CH₂—, —O—, —NH—, —CF₂—, —C(C₁₋₆alkyl)(OH)—, —S—, —C(═O)—,—C(═NOC₀₋₆alkyl)-, —S(═O)—, —S(O₂)— or —S(═O)(NH)—; Y is —CH—, ornitrogen; Q is hydrogen; halogen; C₁₋₆alkyl, unsubstituted or once ortwice substituted by amino or hydroxy, provided that di-substitution isnot on the same carbon; amino(CH₂)₂₋₆aminosulfonyl;2-amino-4,5-dihydro-1,3-oxazol-4-yl(CH₂)₁₋₆; carboxy(CH₂)₁₋₆;phenylsulfonyl; piperidin-4-yl-carbonyl; 1H-pyrazol-3-yl;pyrrolidin-3-yloxy; piperidin-4-yloxy; amino(CH₂)₂₋₆—O—; or NR¹²R¹³,wherein one of R¹² and R¹³ is hydrogen, C₁₋₆alkyl, or hydroxy(CH₂)₂₋₆,and the other one is {1-[amino(CH₂)₀₋₆]-3,3-difluorocyclobutyl}(CH₂)₁₋₆;guanidino(CH₂)₂₋₆; (S—C₁₋₆alkylsulfonimidoyl)(CH₂)₂₋₆;2-oxa-6-aza-spiro[3.4]oct-8-yl;{3-[amino(CH₂)₀₋₆]tetrahydrofuran-3-yl}(CH₂)₁₋₆;3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;3-amino-1,1-dioxidothietan-3-ylmethyl;3-(aminomethyl)thietan-3-ylmethyl;(1,1-dioxidothiomorpholin-4-yl)ethyl;C₀₋₆alkyl(oxetanyl)N(CH₂)₂₋₆; 4,5-dihydro-1H-imidazol-2-yl;amino(CH₂)₂₋₆—O—(CH₂)₂₋₆; amino(CH₂)₂₋₁₀;amino(CH₂)₁₋₆difluoromethyl(CH₂)₁₋₆;amino(CH₂)₁₋₆difluoromethyldifluoromethyl(CH₂)₁₋₆;amino(CH₂)₁₋₆fluoromethyl(CH₂)₁₋₆; amino(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆;amino(CH₂)₀₋₆oxetanyl(CH₂)₁₋₆; amino(CH₂)₂₋₆sulfanyl(CH₂)₂₋₆;amino(CH₂)₂₋₆sulfonyl(CH₂)₂₋₆; amino(CH₂)₀₋₆carbonyl(CH₂)₀₋₆;aminocycloalkyl(CH₂)₀₋₆; 2-aminodihydrooxazol-4-yl(CH₂)₁₋₆;2-aminodihydrooxazol-5-yl(CH₂)₁₋₆;(2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl; aminophenyl;4-aminotetrahydropyran-4-yl(CH₂)₁₋₆; azetidin-2-yl(CH₂)₁₋₆;azetidin-3-yl(CH₂)₀₋₆; azetidinylcarbonyl; C₁₋₆alkoxy(CH₂)₂₋₆;C₁₋₆alkoxy(CH₂)₂₋₆amino(CH₂)₂₋₆; C₁₋₆alkyl; C₁₋₆alkylamino(CH₂)₂₋₆;C₁₋₆alkylaminocarbonyl(CH₂)₀₋₆; C₁₋₆alkylaminooxetanyl(CH₂)₁₋₆;C₁₋₆alkylcarbonyl; C₁₋₆alkylcarbonylamino(CH₂)₂₋₆;C₁₋₆alkylcarbonylamino(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆;C₁₋₆alkylsulfinyl(CH₂)₂₋₆; C₁₋₆alkylsulfonyl; carboxy(CH₂)₁₋₆;cyano(CH₂)₁₋₆; diC₁₋₆alkylamino(CH₂)₂₋₆;diC₁₋₆alkylaminocarbonyl;difluoromethyl(CH₂)₁₋₆amino(CH₂)₂₋₆; hydrogen; hydroxy(CH₂)₂₋₁₀;hydroxy(CH₂)₂₋₆amino(CH₂)₂₋₆; hydroxy(CH₂)₁₋₆carbonyl;hydroxy(CH₂)₀₋₆oxetanyl(CH₂)₁₋₆; hydroxy(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆;hydroxycycloalkyl; isoxazolyl; morpholin-2-yl(CH₂)₁₋₆;morpholin-4-yl(CH₂)₂₋₆; oxetanyl(CH₂)₀₋₆; N-oxetanylpyrrolidin-3-yl;oxo-pyrrolidinylcarbonyl; phenylaminocarbonyl;phenyl(CH₂)₀₋₆aminooxetanyl(CH₂)₁₋₆; phenylcarbonyl;piperazinyl(CH₂)₂₋₆; piperidin-1-yl(CH₂)₂₋₆; piperidin-2-yl(CH₂)₁₋₆;piperidin-3-yl(CH₂)₀₋₆; piperidin-4-yl(CH₂)₀₋₆; piperidinylcarbonyl;pyrazinylcarbonyl; pyrazol-3-yl; pyridazinylcarbonyl;pyridinyl(CH₂)₀₋₆carbonyl; pyridinylamino(CH₂)₂₋₆; pyrrolidin-3-yl,unsubstituted or 4-substituted by halogen; pyrrolidin-4-yl,unsubstituted or 3-substituted by hydroxy or C₁₋₆alkoxy;pyrrolidin-2-yl(CH₂)₁₋₆; pyrrolidinylcarbonyl; tetrahydrofuran-3-yl;tetrahydropyran-4-yl; tetrazolyl(CH₂)₂₋₆;trifluoromethylcarbonylamino(CH₂)₁₋₆oxetanyl; trifluoromethylsulfonyl;

 wherein R¹⁴ is hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₁₋₆; R¹⁵ is hydroxy,C₁₋₆alkyl, hydroxy(CH₂)₁₋₆ or amino; and R¹⁶ is C₁₋₆alkyl,trifluoromethyl, hydroxy(CH₂)₁₋₆, amino(CH₂)₁₋₆, aminocarboxy orcarboxy(CH₂)₁₋₆;

 wherein R¹⁷ is hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₁₋₆; R¹⁸ ishydroxy(CH₂)₁₋₆ or C₁₋₆alkyl; R¹⁹ is hydroxy(CH₂)₁₋₆, amino(CH₂)₁₋₆,carboxy or aminocarboxy(CH₂)₀₋₆; or

 wherein R²⁰ is hydrogen or C₁₋₆alkyl; R²¹ is C₁₋₆alkyl; R²² isC₁₋₆alkoxy or amino; R¹² and R¹³, with the nitrogen atom to which theyare attached, may form a pyrrolidinyl, piperazinyl, piperidinyl,morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which maybe unsubstituted, once or twice substituted by a group selected fromhalogen, C₁₋₆alkyl, C₁₋₆alkoxy, gemdimethyl, amino, aminocarbonyl,hydroxy, oxetanylamino, C₁₋₆alkylpiperazinyl, and amino(CH₂)₁₋₆; R¹² andR¹³, with the nitrogen atom to which they are attached may form a bridgering or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl,2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl,(4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-5-yl, 2-aza-bicyclo[2.1.1]hexan-2-yl, and 3-aza-bicyclo[3.1.0]hexan-3-yl; which maybe unsubstituted or further substituted by amino; and pharmaceuticallyacceptable salt and stereoisomers thereof.
 2. The compound according toclaim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ ishydrogen, halogen or C₁₋₆alkyl; R² is hydrogen, halogen or C₁₋₆alkyl; R³is hydrogen, halogen or C₁₋₆alkyl; R⁴ is hydrogen or C₁₋₆alkyl; R⁵ ishydrogen; R⁶ is hydrogen, halogen, hydroxy, C₁₋₆alkoxy, morpholinyl or4-C₀₋₆alkylpiperazin-1-yl; R⁷ is hydrogen, halogen, C₁₋₆alkyl,C₁₋₆alkoxy, phenoxy or hydroxy(CH₂)₂₋₆—O—; R⁸ is hydrogen, halogen orC₁₋₆alkoxy; R⁹ is hydrogen or C₁₋₆alkyl; R¹⁰ is hydrogen; A is nitrogenor —C—R¹¹, wherein R¹¹ is hydrogen, halogen, C₁₋₆ alkyl, cycloalkyl,C₁₋₆alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy,C₁₋₆alkoxy(CH₂)₁₋₆—O—, difluoromethoxy, cyano, nitro, amino, vinyl,acetylenyl, aminocarbonyl, hydroxy(CH₂)₂₋₆—O—, C₁₋₆alkylsulfinyl,hydroxy(CH₂)₁₋₆, deuteratedC₁₋₆alkyl, carboxyl, alkoxycarbonyl, hydroxy,difluoromethyl, —CH(hydroxy)C₁₋₆alkyl or C₁₋₆alkylsulfanyl; X is S, S═O,SO₂ or S(O)NH; Y is —CH— or nitrogen; Q is C₁₋₆alkyl, unsubstituted oronce substituted by amino; amino(CH₂)₂₋₆aminosulfonyl;2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl; carboxy(CH₂)₁₋₆;phenylsulfonyl; piperidin-4-yl-carbonyl; 1H-pyrazol-3-yl;pyrrolidin-3-yloxy; piperidin-4-yloxy; amino(CH₂)₂₋₆—O—; or NR¹²R¹³,wherein one of R¹² and R¹³ is hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₂₋₆,and the other one is {1-[amino(CH₂)₀₋₆]-3,3-difluorocyclobutyl}(CH₂)₁₋₆;(S—C₁₋₆alkylsulfonimidoyl)(CH₂)₂₋₆;{3-[amino(CH₂)₀₋₆]tetrahydrofuran-3-yl}(CH₂)₁₋₆;(2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl;3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;3-(aminomethyl)thietan-3-ylmethyl; (1,1-dioxidothiomorpholin-4-yl)ethyl;C₀₋₆alkyl(oxetanyl)N(CH₂)₂₋₆; 4,5-dihydro-1H-imidazol-2-yl;amino(CH₂)₂₋₆—O—(CH₂)₂₋₆; amino(CH₂)₂₋₁₀; amino(CH₂)₀₋₆carbonyl(CH₂)₀₋₆;amino(CH₂)₁₋₆difluoromethyl(CH₂)₁₋₆;amino(CH₂)₁₋₆difluoromethyldifluoromethyl(CH₂)₁₋₆;amino(CH₂)₁₋₆fluoromethyl(CH₂)₁₋₆; amino(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆;amino(CH₂)₀₋₆oxetanyl(CH₂)₁₋₆; amino(CH₂)₂₋₆sulfanyl(CH₂)₂₋₆;amino(CH₂)₂₋₆sulfonyl(CH₂)₂₋₆; 1-aminocyclobutylmethyl;2-aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl;1-aminocyclohexylmethyl; 2-aminocyclopentyl; 1-aminocyclopropylethyl;1-aminocyclopropylmethyl; (2-amino-4,5-dihydro-oxazol-5-yl)(CH₂)₁₋₆,(2-amino-4,5-dihydro-oxazol-4-yl)(CH₂)₁₋₆; aminophenyl;4-aminotetrahydropyran-4-yl(CH₂)₁₋₆; azetidin-2-yl(CH₂)₁₋₆;azetidin-3-yl(CH₂)₀₋₆; azetidin-3-ylcarbonyl; C₁₋₆alkoxy(CH₂)₂₋₆;C₁₋₆alkoxy(CH₂)₂₋₆amino(CH₂)₂₋₆; C₁₋₆alkyl; C₁₋₆alkylamino(CH₂)₂₋₆;C₁₋₆alkylaminooxetanyl(CH₂)₁₋₆; C₁₋₆alkylcarbonyl;C₁₋₆alkylaminocarbonyl(CH₂)₀₋₆; C₁₋₆alkylcarbonylamino(CH₂)₂₋₆;C₁₋₆alkylcarbonylamino(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆;C₁₋₆alkylsulfinyl(CH₂)₂₋₆; C₁₋₆alkylsulfonyl; carboxy(CH₂)₁₋₆;cyano(CH₂)₁₋₆; diC₁₋₆alkylamino(CH₂)₂₋₆; diC₁₋₆alkylaminocarbonyl;difluoromethyl(CH₂)₁₋₆amino(CH₂)₂₋₆; hydrogen; hydroxy(CH₂)₂₋₁₀;hydroxy(CH₂)₂₋₆amino(CH₂)₂₋₆; hydroxy(CH₂)₁₋₆carbonyl;hydroxy(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆; hydroxy(CH₂)₀₋₆oxetanyl(CH₂)₁₋₆;4-hydroxycyclohexyl; isoxazol-3-yl; morpholin-2-yl(CH₂)₁₋₆;morpholin-4-yl(CH₂)₂₋₆; 2-oxa-6-aza-spiro[3.4]oct-8-yl;oxetanyl(CH₂)₀₋₆; N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidinylcarbonyl;phenylaminocarbonyl; phenyl(CH₂)₀₋₆aminooxetanyl(CH₂)₁₋₆;phenylcarbonyl; piperazinyl(CH₂)₂₋₆; piperidin-1-yl(CH₂)₂₋₆;piperidin-2-yl(CH₂)₁₋₆; piperidin-3-yl(CH₂)₀₋₆; piperidin-4-yl(CH₂)₀₋₆;piperidinylcarbonyl; pyrazinylcarbonyl; pyrazol-3-yl;pyridazinylcarbonyl; pyridinyl(CH₂)₀₋₆carbonyl; pyridinylamino(CH₂)₂₋₆;pyrrolidin-3-yl, unsubstituted or 4-substituted by halogen;pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy orC₁₋₆alkoxy; pyrrolidin-2-yl(CH₂)₁₋₆; pyrrolidinylcarbonyl;tetrahydrofuran-3-yl; tetrahydropyran-4-yl; tetrazolyl(CH₂)₂₋₆;trifluoromethylcarbonylamino(CH₂)₁₋₆oxetanyl; trifluoromethylsulfonyl;

 wherein R¹⁴ is hydrogen or C₁₋₆alkyl; R¹⁵ is hydroxy, C₁₋₆alkyl oramino; and R¹⁶ is C₁₋₆alkyl, trifluoromethyl, hydroxy(CH₂)₁₋₆,amino(CH₂)₁₋₆, aminocarbonyl or carboxy(CH₂)₁₋₆;

 wherein R¹⁷ is hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₁₋₆; R¹⁸ ishydroxy(CH₂)₁₋₆ or C₁₋₆alkyl; R¹⁹ is hydroxy(CH₂)₁₋₆, amino(CH₂)₁₋₆,carboxy or aminocarbonyl(CH₂)₀₋₆; or

 wherein R²⁰ is hydrogen or C₁₋₆alkyl; R²¹ is C₁₋₆alkyl; R²² isC₁₋₆alkoxy or amino; R¹² and R¹³, with the nitrogen atom to which theyare attached, may form a pyrrolidinyl, piperazinyl, piperidinyl,morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which maybe unsubstituted, once or twice substituted by a group selected fromhalogen, C₁₋₆alkyl, C₁₋₆alkoxy, gemdimethyl, amino, aminocarbonyl,hydroxy, oxetanylamino, C₁₋₆alkylpiperazinyl, and amino(CH₂)₁₋₆; or R¹²and R¹³, with the nitrogen atom to which they are attached may form abridge ring or a spiral ring selected from2-oxa-6-aza-spiro[3.4]octan-6-yl,2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl,(4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-5-yl,2-aza-bicyclo[2.1.1]hexan-2-yl and 3-aza-bicyclo[3.1.0]hexan-3-yl; whichmay be unsubstituted or further substituted by amino.
 3. The compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof,wherein R¹, R² or R³ are hydrogen, fluoro, chloro or methyl; R⁴ ishydrogen or methyl; R⁵ is hydrogen; R⁶ is hydrogen, fluoro, hydroxy,methoxy, morpholinyl or 4-(propan-2-yl)piperazin-1-yl; R⁷ is hydrogen,fluoro, chloro, methyl, methoxy, ethoxy, hydroxyethoxy or phenoxy; R⁸ ishydrogen, fluoro or methoxy; R⁹ is hydrogen or methyl; R¹⁰ is hydrogen;A is nitrogen or —C—R¹¹, wherein R¹¹ is hydrogen, fluoro, chloro, bromo,methyl, ethyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy,pyridinyloxy, methoxyethoxy, difluoromethoxy, cyano, nitro, amino,vinyl, acetylenyl, aminocarbonyl, hydroxyethoxy, methylsulfanyl,methylsulfinyl, hydroxymethyl, deuteratedmethyl, carboxyl,methoxycarbonyl, hydroxy, difluoromethyl, methylCH(hydroxy)- ormethylsulfonyl; X is S, S═O, SO₂ or S(O)NH; Y is —CH— or nitrogen; Q is2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl; aminoethoxy;aminoethylaminosulfonyl; aminopropyl; carboxyethyl; methyl;phenylsulfonyl; piperidin-4-yl-carbonyl; piperidin-4-yloxy;1H-pyrazol-3-yl; pyrrolidin-3-yloxy; or NR¹²R¹³, wherein one of R¹² andR¹³ is hydrogen, methyl or hydroxyethyl, and the other one isaminobutyl; aminocarbonylethyl; aminocarbonylmethyl;1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl;4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl;1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; aminodecyl;(2-amino-4,5-dihydro-oxazol-5-yl)methyl;(2-amino-4,5-dihydro-oxazol-4-yl)methyl; aminoethoxyethyl; aminoethyl;aminoethylcarbonyl; aminoethylfluoromethylmethyl;aminoethylsulfanylethyl; aminoethylsulfonylethyl; aminoheptyl;aminohexyl; aminomethylcarbonyl;(1-aminomethyl-3,3-difluorocyclobutyl)methyl;aminomethyldifluoromethyldifluoromethylmethyl;aminomethyldifluoromethylmethyl;(2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl;3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl;aminomethyloxetanyl; aminomethyloxetanylmethyl;3-(aminomethyl)thietan-3-ylmethyl; aminononyl; aminooctyl;aminooxetanylethyl; aminooxetanylmethyl; aminopentyl; aminophenyl;aminopropyl; 4-aminotetrahydropyran-4-ylmethyl;3-aminotetrahydrofuran-3-ylmethyl;azetidin-3-yl; azetidin-3-ylcarbonyl;azetidin-2-ylmethyl; azetidin-3-ylmethyl; carboxyethyl; carboxymethyl;cyanoethyl; difluoromethylmethylaminoethyl;4,5-dihydro-1H-imidazol-2-yl; dimethylaminocarbonyl; dimethylaminoethyl;(1,1-dioxidothiomorpholin-4-yl)ethyl; ethyl; ethylaminocarbonyl;ethylaminoethyl; ethylaminooxetanylmethyl; ethyl (oxetanyl)aminoethyl;hydrogen; 4-hydroxycyclohexyl; hydroxyethyl; hydroxyethylaminoethyl;hydroxyethyloxetanyl; hydroxymethylcarbonyl;hydroxymethyloxetanylmethyl; hydroxynonyl; hydroxypropyl; isoxazol-3-yl;methoxyethyl; methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl;methylaminoethyl; methylcarbonyl; methylcarbonylaminoethyl;methylcarbonylaminomethyloxetanylmethyl; methylcarbonylaminopropyl;methylsulfinylethyl; 2-(S-methylsulfonimidoyl)ethyl; methylsulfonyl;morpholin-4-ylethyl; morpholin-2-ylmethyl;2-oxa-6-aza-spiro[3.4]oct-8-yl; oxetanyl; oxetanylaminoethyl;oxetanylaminopropyl; oxetanylmethyl; N-oxetanylpyrrolidin-3-yl;oxo-pyrrolidin-4-ylcarbonyl; phenylaminocarbonyl; phenylcarbonyl;phenylmethylaminooxetanylmethyl; piperazin-1-ylethyl;piperidin-2-ylcarbonyl; piperidin-3-ylcarbonyl; piperidin-4-ylcarbonyl;piperidin-3-yl; piperidin-4-yl; piperidin-1-ylethyl;piperidin-2-ylmethyl; pyrazin-2-ylcarbonyl; pyrazol-3-yl;pyridazin-3-ylcarbonyl; pyridine-2-ylmethylcarbonyl;pyridine-2-ylaminoethyl; pyridine-2-ylcarbonyl; pyridine-3-ylcarbonyl;pyrrolidin-3-yl, unsubstituted or 4-substituted by fluoro;pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy or methoxy;pyrrolidin-2-ylmethyl; pyrrolidin-2-ylcarbonyl; tetrahydrofuran-3-yl;tetrahydropyran-4-yl; tetrazolylethyl; trifluoromethylsulfonyl;trifluoromethylcarbonylaminomethyloxetanyl;

 wherein R¹⁴ is hydrogen or methyl; R¹⁵ is hydroxy, methyl or amino; andR¹⁶ is methyl, trifluoromethyl, hydroxymethyl, hydroxyethyl,aminomethyl, aminocarbonyl or carboxymethyl;

 wherein R¹⁷ is hydrogen, methyl or hydroxymethyl; R¹⁸ is hydroxymethylor methyl; R¹⁹ is hydroxymethyl, aminomethyl, carboxy, aminocarbonyl oraminocarbonylmethyl; or

 wherein R²⁰ is hydrogen or methyl; R²¹ is methyl or ethyl; R²² ismethoxy or amino; R¹² and R¹³, with the nitrogen atom to which they areattached, may form a pyrrolidinyl, piperazinyl, piperidinyl,morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which maybe unsubstituted, once or twice substituted by a group selected fromfluoro, methyl, methoxy, gemdimethyl, amino, aminocarbonyl, hydroxy,oxetanylamino, methylpiperazinyl and aminomethyl; or R¹² and R¹³, withthe nitrogen atom to which they are attached may form a bridge ring or aspiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl,2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl,(4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-5-yl,2-aza-bicyclo[2.1.1]hexan-2-yl or 3-aza-bicyclo[3.1.0]hexan-3-yl; whichmay be unsubstituted or further substituted by amino.
 4. The compoundaccording to any one of claim 1 or a pharmaceutically acceptable saltthereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ arehydrogen; A is —C—R¹¹, wherein R¹¹ is hydrogen, halogen or C₁₋₆alkyl; Xis S; Y is —CH— or nitrogen; Q is NR¹²R¹³, wherein one of R¹² and R¹³ ishydrogen, and the other one is amino(CH₂)₂₋₆;amino(CH₂)₁₋₆difluoromethyl(CH₂)₁₋₆; amino(CH₂)₀₋₆oxetanyl(CH₂)₁₋₆ orhydrogen; or R¹² and R¹³, with the nitrogen atom to which they areattached, may form a pyrrolidinyl ring, which may be once substituted byamino.
 5. The compound according to claim 4 or a pharmaceuticallyacceptable salt thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ andR¹⁰ are hydrogen; A is —C—R¹¹, wherein R¹¹ is hydrogen, chloro ormethyl; Q is NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen, and theother one is aminoethyl; aminomethyldifluoromethylmethyl;aminomethyloxetanylmethyl; aminooxetanylmethyl or hydrogen; or R¹² andR¹³, with the nitrogen atom to which they are attached, may form apyrrolidinyl ring, which may be once substituted by amino.
 6. Thecompound according to any one of claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ andR¹⁰ are hydrogen; A is —C—R¹¹, wherein R¹¹ is hydrogen, halogen,C₁₋₆alkyl, hydroxy(CH₂)₁₋₆, deuteratedmethyl or carboxyl; X is S═O; Y is—CH— or nitrogen; Q is NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen;and the other one is amino(CH₂)₂₋₆; amino(CH₂)₁₋₆difluoromethyl(CH₂)₁₋₆;amino(CH₂)₁₋₆fluoromethyl(CH₂)₁₋₆; amino(CH₂)₁₋₆oxetanyl;amino(CH₂)₁₋₆oxetanyl(CH₂)₁₋₆; aminooxetanyl(CH₂)₁₋₆; hydroxy(CH₂)₂₋₁₀;phenyl(CH₂)₁₋₆aminooxetanyl(CH₂)₁₋₆; pyrrolidin-3-yl, 4-substituted byhalogen; or

 wherein R¹⁴ is hydrogen, R¹⁵ is hydroxy, and R¹⁶ is hydroxy(CH₂)₁₋₆; orR¹² and R¹³, with the nitrogen atom to which they are attached, may forma pyrrolidinyl ring, which may be once or twice substituted by a groupselected from halogen, amino and hydroxyl.
 7. The compound according toclaim 6 or a pharmaceutically acceptable salt thereof, wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are hydrogen; A is —C—R¹¹, whereinR¹¹ is hydrogen, chloro, methyl, hydroxymethyl, deuteratedmethyl orcarboxyl; Q is NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen, and theother one is aminoethyl; aminomethyldifluoromethylmethyl;aminomethylfluoromethylmethyl; aminomethyloxetanyl;aminomethyloxetanylmethyl; aminooxetanylmethyl; aminopropyl;hydroxyethyl; phenylmethylaminooxetanylmethyl; pyrrolidin-3-yl,4-substituted by fluoro; or

 wherein R¹⁴ is hydrogen, R¹⁵ is hydroxy, and R¹⁶ is hydroxymethyl; orR¹² and R¹³, with the nitrogen atom to which they are attached, may forma pyrrolidinyl ring, which may be once or twice substituted by a groupselected from fluoro, amino and hydroxyl.
 8. The compound according toany one of claim 1 or a pharmaceutically acceptable salt thereof,wherein R¹, R², and R³ are hydrogen, halogen or C₁₋₆alkyl; R⁴ ishydrogen or C₁₋₆alkyl; R⁵ is hydrogen; R⁶ is hydrogen, halogen, hydroxy,C₁₋₆alkoxy, morpholinyl or 4-(propan-2-yl)piperazin-1-yl; R⁷ ishydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy(CH₂)₂₋₆—O—, orphenoxy; R⁸ is hydrogen, halogen or C₁₋₆alkoxy; R⁹ is hydrogen orC₁₋₆alkyl; R¹⁰ is hydrogen; A is nitrogen or —C—R¹¹, wherein R¹¹ ishydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, trifluoromethyl,trifluoromethoxy, pyridinyloxy, C₁₋₆alkoxy(CH₂)₁₋₆—O—, difluoromethoxy,nitro, cycloalkyl, cyano, amino, vinyl, acetylenyl, aminocarbonyl,hydroxy(CH₂)₂₋₆—O—, C₁₋₆alkylsulfanyl, C₁₋₆alkylsulfinyl,hydroxy(CH₂)₁₋₆, deuteratedmethyl, carboxyl, C₁₋₆alkoxycarbonyl,hydroxy, difluoromethyl or methylCH(hydroxy)- ; X is SO₂; Y is —CH— ornitrogen; Q is 2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl;amino(CH₂)₂₋₆—O—; amino(CH₂)₂₋₆aminosulfonyl; C₁₋₆alkyl, unsubstitutedor once substituted by amino; carboxy(CH₂)₁₋₆; phenylsulfonyl;piperidin-4-yl-carbonyl; piperidin-4-yloxy; 1H-pyrazol-3-yl;pyrrolidin-3-yloxy; or NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen,C₁₋₆alkyl or hydroxy(CH₂)₂₋₆; and the other one is{1-[amino(CH₂)₀₋₆]-3,3 difluorocyclobutyl}(CH₂)₁₋₆;(S—C₁₋₆alkylsulfonimidoyl)(CH₂)₂₋₆; 3-aminotetrahydrofuran-3-yl(CH₂)₁₋₆;(2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl;3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;3-(aminomethyl)thietan-3-ylmethyl; (1,1-dioxidothiomorpholin-4-yl)ethyl;C₀₋₆alkyl(oxetanyl)N(CH₂)₂₋₆; 4,5-dihydro-1H-imidazol-2-yl;amino(CH₂)₂₋₆—O—(CH₂)₂₋₆; amino(CH₂)₂₋₁₀; amino(CH₂)₁₋₆carbonyl;aminocarbonyl(CH₂)₁₋₆; amino(CH₂)₁₋₆difluoromethyl(CH₂)₁₋₆;amino(CH₂)₁₋₆difluoromethyldifluoromethyl(CH₂)₁₋₆;amino(CH₂)₁₋₆fluoromethyl(CH₂)₁₋₆; amino(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆;amino(CH₂)₀₋₆oxetanyl(CH₂)₁₋₆; amino(CH₂)₂₋₆sulfanyl(CH₂)₂₋₆;amino(CH₂)₂₋₆sulfonyl(CH₂)₂₋₆; 1-aminocyclobutylmethyl;2-aminocyclohexyl; 3-aminocyclohexyl; 4-aminocyclohexyl;1-aminocyclohexylmethyl; 2-aminocyclopentyl; 1-aminocyclopropylethyl;1-aminocyclopropylmethyl; (2-amino-4,5-dihydro-oxazol-5-yl)(CH₂)₁₋₆;(2-amino-4,5-dihydro-oxazol-4-yl)(CH₂)₁₋₆; aminophenyl;4-aminotetrahydropyran-4-yl(CH₂)₁₋₆; azetidin-2-yl(CH₂)₁₋₆;azetidin-3-yl(CH₂)₀₋₆; azetidin-3-ylcarbonyl; C₁₋₆alkoxy(CH₂)₂₋₆;C₁₋₆alkoxy(CH₂)₂₋₆amino(CH₂)₂₋₆; C₁₋₆alkyl; C₁₋₆alkylamino(CH₂)₂₋₆; C₁₋₆alkylaminooxetanyl(CH₂)₁₋₆; C₁₋₆ alkylcarbonyl;C₁₋₆alkylcarbonylamino(CH₂)₂₋₆;C₁₋₆alkylcarbonylamino(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆;C₁₋₆alkylsulfinyl(CH₂)₂₋₆; C₁₋₆alkylsulfonyl; carboxy(CH₂)₁₋₆;cyano(CH₂)₁₋₆; C₁₋₆alkylaminocarbonyl(CH₂)₀₋₆; diC₁₋₆alkylamino(CH₂)₂₋₆;diC₁₋₆alkylaminocarbonyl; difluoromethyl(CH₂)₁₋₆amino(CH₂)₂₋₆; hydrogen;hydroxy(CH₂)₂₋₁₀; hydroxy(CH₂)₂₋₆amino(CH₂)₂₋₆; hydroxy(CH₂)₁₋₆carbonyl;hydroxy(CH₂)₁₋₆oxetanyl(CH₂)₀₋₆; 4-hydroxycyclohexyl; isoxazol-3-yl;morpholin-2-yl(CH₂)₁₋₆; morpholin-4-yl(CH₂)₂₋₆;2-oxa-6-aza-spiro[3.4]oct-8-yl; oxetanyl(CH₂)₀₋₆;N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidin-4-ylcarbonyl;phenylaminocarbonyl; phenyl(CH₂)₁₋₆aminooxetanyl(CH₂)₁₋₆;phenylcarbonyl; piperazinyl(CH₂)₂₋₆; piperidin-1-yl(CH₂)₂₋₆;piperidin-2-yl(CH₂)₁₋₆; piperidin-3-yl(CH₂)₀₋₆; piperidin-4-yl(CH₂)₀₋₆;piperidin-2-ylcarbonyl; piperidin-3-ylcarbonyl; piperidin-4-ylcarbonyl;pyrazin-2-ylcarbonyl; pyrazol-3-yl; pyridazin-3-ylcarbonyl;pyridine-2-yl(CH₂)₀₋₆carbonyl; pyridine-3-yl(CH₂)₀₋₆carbonyl;pyridine-2-ylamino(CH₂)₂₋₆; pyrrolidin-3-yl, unsubstituted or4-substituted by halogen; pyrrolidin-4-yl, unsubstituted or3-substituted by hydroxy or C₁₋₆alkoxy; pyrrolidin-2-yl(CH₂)₁₋₆;pyrrolidin-2-ylcarbonyl; tetrahydrofuran-3-yl; tetrahydropyran-4-yl;tetrazolyl(CH₂)₂₋₆; trifluoromethylcarbonylamino(CH₂)₁₋₆oxetanyl;trifluoromethylsulfonyl;

 wherein R¹⁴ is hydrogen or C₁₋₆alkyl; R¹⁵ is hydroxy, C₁₋₆alkyl oramino; and R¹⁶ is C₁₋₆alkyl, trifluoromethyl, hydroxy(CH₂)₁₋₆,amino(CH₂)₁₋₆, aminocarbonyl or carboxy(CH₂)₁₋₆;

 wherein R¹⁷ is hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₁₋₆; R¹⁸ ishydroxy(CH₂)₁₋₆ or C₁₋₆alkyl; R¹⁹ is hydroxy(CH₂)₁₋₆, amino(CH₂)₁₋₆,carboxy or aminocarbonyl(CH₂)₀₋₆; or

 wherein R²⁰ is hydrogen or C₁₋₆alkyl; R²¹ is C₁₋₆alkyl; R²² isC₁₋₆alkoxy or amino; R¹² and R¹³, with the nitrogen atom to which theyare attached, may form a pyrrolidinyl, piperazinyl, piperidinyl,morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which maybe unsubstituted, once or twice substituted by a group selected fromhalogen, C₁₋₆alkyl, C₁₋₆alkoxy, gemdimethyl, amino, aminocarbonyl,hydroxy, oxetanylamino, C₁₋₆alkylpiperazinyl and amino(CH₂)₁₋₆; or R¹²and R¹³, with the nitrogen atom to which they are attached may form abridge ring or a spiral ring selected from2-oxa-6-aza-spiro[3.4]octan-6-yl,2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl,(4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-5-yl,2-aza-bicyclo[2.1.1]hexan-2-yl or 3-aza-bicyclo[3.1.0]hexan-3-yl; whichmay be unsubstituted or further substituted by amino.
 9. The compoundaccording to claim 8 or a pharmaceutically acceptable salt thereof,wherein R¹, R², and R³ are hydrogen, fluoro, chloro or methyl; R⁴ ishydrogen or methyl; R⁵ is hydrogen; R⁶ is hydrogen, fluoro, hydroxy,methoxy, morpholinyl or 4-(propan-2-yl)piperazin-1-yl; R⁷ is hydrogen,fluoro, chloro, methyl, methoxy, hydroxyethoxy, or phenoxy; R⁸ ishydrogen, fluoro or methoxy; R⁹ is hydrogen or methyl; R¹⁰ is hydrogen;A is nitrogen or —C—R¹¹, wherein R¹¹ is hydrogen, fluoro, chloro, bromo,methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy,methoxyethoxy, difluoromethoxy, nitro, cyclopropyl, cyano, amino, vinyl,acetylenyl, aminocarbonyl, hydroxyethoxy, methylsulfanyl,methylsulfinyl, hydroxymethyl, deuteratedmethyl, carboxyl,methoxycarbonyl, hydroxy, difluoromethyl or methylCH(hydroxy)-; Y is—CH— or nitrogen; Q is 2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl;aminoethoxy; aminoethylaminosulfonyl; aminopropyl; carboxyethyl; methyl;phenylsulfonyl; piperidin-4-yl-carbonyl; piperidin-4-yloxy;1H-pyrazol-3-yl; pyrrolidin-3-yloxy; or NR¹²R¹³, wherein one of R¹² andR¹³ is hydrogen, methyl or hydroxyethyl, and the other one isaminobutyl; aminocarbonylethyl; aminocarbonylmethyl;1-aminocyclobutylmethyl; 2-aminocyclohexyl; 3-aminocyclohexyl;4-aminocyclohexyl; 1-aminocyclohexylmethyl; 2-aminocyclopentyl;1-aminocyclopropylethyl; 1-aminocyclopropylmethyl; aminodecyl;(2-amino-4,5-dihydro-oxazol-5-yl)methyl;(2-amino-4,5-dihydro-oxazol-4-yl)methyl; aminoethoxyethyl; aminoethyl;aminoethylcarbonyl; aminoethylfluoromethylmethyl;aminoethylsulfanylethyl; aminoethylsulfonylethyl; aminoheptyl;aminohexyl; aminomethylcarbonyl;(1-aminomethyl-3,3-difluorocyclobutyl)methyl;aminomethyldifluoromethyldifluoromethylmethyl;aminomethyldifluoromethylmethyl;(2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl;3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;aminomethylfluoromethylethyl; aminomethylfluoromethylmethyl;aminomethyloxetanyl; aminomethyloxetanylmethyl;3-(aminomethyl)thietan-3-ylmethyl; aminononyl; aminooctyl;aminooxetanylethyl; aminooxetanylmethyl; aminopentyl; aminophenyl;aminopropyl; 4-aminotetrahydropyran-4-ylmethyl;3-aminotetrahydrofuran-3-ylmethyl; azetidin-3-yl; azetidin-3-ylcarbonyl;azetidin-2-ylmethyl; azetidin-3-ylmethyl; carboxyethyl; carboxymethyl;cyanoethyl; difluoromethylmethylaminoethyl;4,5-dihydro-1H-imidazol-2-yl; dimethylaminocarbonyl; dimethylaminoethyl;(1,1-dioxidothiomorpholin-4-yl)ethyl; ethyl; ethylaminocarbonyl;ethylaminoethyl; ethylaminooxetanylmethyl; ethyl (oxetanyl)aminoethyl;hydrogen; 4-hydroxycyclohexyl; hydroxyethyl; hydroxyethylaminoethyl;hydroxyethyloxetanyl; hydroxymethylcarbonyl;hydroxymethyloxetanylmethyl; hydroxynonyl; hydroxypropyl; isoxazol-3-yl;methoxyethyl; methoxyethylaminoethyl; methyl; methylaminocarbonylmethyl;methylaminoethyl; methylcarbonyl; methylcarbonylaminoethyl;methylcarbonylaminomethyloxetanylmethyl; methylcarbonylaminopropyl;methylsulfinylethyl; 2-(S-methylsulfonimidoyl)ethyl; methylsulfonyl;morpholin-4-ylethyl; morpholin-2-ylmethyl;2-oxa-6-aza-spiro[3.4]oct-8-yl; oxetanyl; oxetanylaminoethyl;oxetanylaminopropyl; oxetanylmethyl; N-oxetanylpyrrolidin-3-yl;oxo-pyrrolidin-4-ylcarbonyl; phenylaminocarbonyl; phenylcarbonyl;phenylmethylaminooxetanylmethyl; piperazin-1-ylethyl;piperidin-2-ylcarbonyl; piperidin-3-ylcarbonyl; piperidin-4-ylcarbonyl;piperidine-3-yl; piperidine-4-yl; piperidin-1-ylethyl;piperidin-2-ylmethyl; pyrazin-2-ylcarbonyl; pyrazol-3-yl;pyridazin-3-ylcarbonyl; pyridine-2-ylmethylcarbonyl;pyridine-2-ylaminoethyl; pyridine-2-ylcarbonyl; pyridine-3-ylcarbonyl;pyrrolidin-3-yl, unsubstituted or 4-substituted by fluoro;pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy or methoxy;pyrrolidin-2-ylmethyl; pyrrolidin-2-ylcarbonyl; tetrahydrofuran-3-yl;tetrahydropyran-4-yl; tetrazolylethyl; trifluoromethylsulfonyl;trifluoromethylcarbonylaminomethyloxetanyl;

 wherein R¹⁴ is hydrogen or methyl; R¹⁵ is hydroxy, methyl or amino; andR¹⁶ is methyl, trifluoromethyl, hydroxymethyl, hydroxyethyl,aminomethyl, aminocarbonyl or carboxymethyl;

 wherein R¹⁷ is hydrogen, methyl or hydroxymethyl; R¹⁸ is hydroxymethylor methyl; R¹⁹ is hydroxymethyl, aminomethyl, carboxy, aminocarbonyl oraminocarbonylmethyl; or

 wherein R²⁰ is hydrogen or methyl; R²¹ is methyl or ethyl; R²² ismethoxy or amino; R¹² and R¹³, with the nitrogen atom to which they areattached, may form a pyrrolidinyl, piperazinyl, piperidinyl,morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which maybe unsubstituted, once or twice substituted by a group selected fromfluoro, methyl, methoxy, gemdimethyl, amino, aminocarbonyl, hydroxy,oxetanylamino, methylpiperazinyl and aminomethyl; or R¹² and R¹³, withthe nitrogen atom to which they are attached may form a bridge ring or aspiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl,2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl,(4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-5-yl,2-aza-bicyclo[2.1.1]hexan-2-yl or 3-aza-bicyclo[3.1.0]hexan-3-yl; whichmay be unsubstituted or further substituted by amino.
 10. The compoundaccording to any one of claim 1 or a pharmaceutically acceptable saltthereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ arehydrogen; A is —C—R¹¹, wherein R¹¹ is C₁₋₆alkyl; X is S(O)NH; Y is —CH—;Q is NR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen; and the other oneis amino(CH₂)₂₋₆; or R¹² and R¹³, with the nitrogen atom to which theyare attached, may form a pyrrolidinyl ring, which may be twicesubstituted by a group selected from amino and hydroxyl.
 11. Thecompound according to claim 10 or a pharmaceutically acceptable saltthereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ arehydrogen; A is —C—R¹¹, wherein R¹¹ is methyl; Q is NR¹²R¹³, wherein oneof R¹² and R¹³ is hydrogen; and the other one is aminoethyl; or R¹² andR¹³, with the nitrogen atom to which they are attached, may form apyrrolidinyl ring, which may be twice substituted by a group selectedfrom amino and hydroxyl.
 12. The compound according to claim 1 or apharmaceutically acceptable salt thereof, selected from the groupconsisting of:N-[(3-aminooxetan-3-yl)methyl]-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(8-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(9-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(8-chloro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[(3-aminotetrahydrofuran-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;andN-[(4-aminotetrahydro-2H-pyran-4-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine.13. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[(3-aminooxetan-3-yl)methyl]-2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(2-oxa-6-azaspiro[3.4]oct-8-yl)quinolin-4-amine;N-[2-(3-aminooxetan-3-yl)ethyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(5-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-amine;N-[(1-aminocyclohexyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(8-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;andN-{[3-(benzylamino)oxetan-3-yl]methyl}-6-chloro-2-(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine.14. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(7-fluoro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-{[3-({[2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}methyl)oxetan-3-yl]methyl}acetamide;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(8-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;[3-({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}methyl)oxetan-3-yl]methanol;(2S)-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol;and(2R)-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol.15. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-{[1-(aminomethyl)-3,3-difluorocyclobutyl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;trans-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclohexane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclohexane-1,3-diamine;(3R)-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4-dimethylpyrrolidin-3-ol;cis-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclohexane-1,4-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2-difluoropropane-1,3-diamine;N-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2,2-difluoropropane-1,3-diamine;andN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-fluoropropane-1,3-diamine.16. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;[4-{[(3-aminooxetan-3-yl)methyl]amino}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-fluoro-6-methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-amine;N˜1˜-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2-methylpropane-1,2-diamine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(tetrahydro-2H-pyran-4-yl)quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(piperazin-1-yl)ethyl]quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-4-ylmethyl)quinolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]heptane-1,7-diamine;andN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-methylethane-1,2-diamine.17. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N′-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N,N-dimethylethane-1,2-diamine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N,6-dimethylquinolin-4-aminetrifluoroacetate;(3S,4S)-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3,4-diol;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-2-ylmethyl)quinolin-4-amine;4-[4-(1,4-diazepan-1-yl)-6-methylquinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-ethylethane-1,2-diamine;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}ethanol;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-4-yl)quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-3-yl)quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(piperidin-2-ylmethyl)quinolin-4-amine;and2-[(2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}ethyl)amino]ethanol.18. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2,3,3-tetrafluorobutane-1,4-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(2-methoxyethyl)ethane-1,2-diamine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-methylpyrrolidin-3-ol;N-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(oxetan-3-yl)quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[(3R)-tetrahydrofuran-3-yl]quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;andN-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine.19. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(oxetan-3-ylmethyl)quinolin-4-amine;N-[(1-aminocyclobutyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pentane-1,5-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]hexane-1,6-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-1,1,1-trifluoromethanesulfonamidehydrochloride;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyridazine-3-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]benzamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]acetamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-3-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-4-carboxamide;and3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-1,1-dimethylurea.20. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(1,2-oxazol-3-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(˜2˜H_3_)methylquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[6-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;N-[(3-aminooxetan-3-yl)methyl]-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;1-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine;N-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2,2-difluoropropane-1,3-diamine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-[2-(1,1-dioxidothiomorpholin-4-yl)ethyl]-6-methylquinolin-4-amine;N-[2-(2-aminoethoxy)ethyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropane-1,2-diamine;andN˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2-methylpropane-1,2-diamine.21. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,2-diamine;4-[6-methyl-4-(4-methylpiperazin-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;1-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-2-ol;(2S)—N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,2-diamine;(2R)—N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,2-diamine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7,8-difluoro-6-methylquinolin-4-amine;N-(2,2-difluoroethyl)-N′-[2-(1,1-dioxido-2,3-dihydro-1,4benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}oxetan-3-ethanol;N-{[3-(aminomethyl)thietan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;andN-{[3-(aminomethyl)-1,1-dioxidothietan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine.22. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-(4,5-dihydro-1H-imidazol-2-yl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;trans-4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}cyclohexanol;(2S)-2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol;trans-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-methoxypyrrolidin-3-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-[trans-4-methoxypyrrolidin-3-yl]-6-methylquinolin-4-amine;4-{4-[(4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]-6-methylquinolin-2-yl}-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;(3R,4R)-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-(4-methylpiperazin-1-yl)pyrrolidin-3-ol;N-{2-[(2-aminoethyl)sulfanyl]ethyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;1-{1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidin-4-yl}methanamine;and2-{[2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}ethanol.23. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,3-diamine;4-[6-methyl-4-(morpholin-4-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(piperidin-1-yl)ethyl]quinolin-4-amine;1-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-2-ol;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-fluoroquinolin-4-yl]ethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]ethane-1,2-diamine;N-[7-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;N-[8-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;andN-[5-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine.24. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2,2-dimethylpropane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine;N˜2˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropane-1,2-diamine;N˜2˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]butane-1,4-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-nitroquinolin-4-yl]ethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-yl]ethane-1,2-diamine;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-5-fluoro-6-methylquinolin-4-yl]amino}ethanol;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-fluoro-6-methylquinolin-4-yl]amino}ethanol;andN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-fluoro-6-methylquinolin-4-yl]ethane-1,2-diamine.25. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7,8-difluoro-6-methylquinolin-4-yl]ethane-1,2-diamine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-(2-methoxyethyl)-6-methylquinolin-4-amine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidin-4-amine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]pyrrolidin-3-amine;N-[6-(difluoromethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-ethylquinolin-4-amine;2-{[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}ethanol;N-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-N′-methylethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(methylsulfanyl)quinolin-4-yl]propane-1,3-diamine;N-[6-bromo-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;and{4-[(2-aminoethyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}methanol.26. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,3-diol;2,2′-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]imino}diethanol;4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-3-hydroxybutanoic acid;1-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropan-2-ol;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(morpholin-4-yl)ethyl]quinolin-4-amine;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]amino}ethanol;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]nonane-1,9-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]decane-1,10-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]octane-1,8-diamine;9-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}nonan-1-ol;andN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]octane-1,8-diamine.27. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:cis-4-amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-L-alanine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alanine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]benzene-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]benzene-1,4-diamine;(3S)-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol;(3R)-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol;trans-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]cyclopentane-1,2-diamine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidin-3-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N,N,6-trimethylquinolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(trifluoromethoxy)quinolin-4-yl]propane-1,3-diamine;andN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(trifluoromethyl)quinolin-4-yl]propane-1,3-diamine.28. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[6-(difluoromethoxy)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methoxyquinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-8-methylquinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-7-methylquinolin-4-yl]propane-1,3-diamine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-fluoroquinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;(+)-N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine;(−)-N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;and2,2-difluoro-N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine.29. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-2,2-difluoropropane-1,3-diamine;N-[6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;2-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}ethanol;trans-4-amino-1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin-3-ol;(1R,5S,6S)-3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-azabicyclo[3.1.0]hexan-6-amine;trans-4-amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol;and1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin-3-amine.30. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:trans-1-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-4-fluoropyrrolidin-3-amine;trans-4-amino-1-[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]pyrrolidin-3-ol;trans-1-[6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]-4-fluoropyrrolidin-3-amine;2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-azabicyclo[2.1.1]hexan-5-amine;2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;2-(7-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[2-(1-aminocyclopropyl)ethyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(morpholin-2-ylmethyl)quinolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-methylethane-1,2-diamine;andN-(azetidin-2-ylmethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine.31. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine;N-[(1-aminocyclopropyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-(azetidin-3-yl)-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;6-[2-(1,1-dioxido-2,3dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-6-azaspiro[3.4]octan-8-amine;trans-4-amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]pyrrolidin-3-ol;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine;N-(azetidin-3-yl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]azetidin-3-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]prolinamide;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-(trans-4-fluoropyrrolidin-3-yl)-6-methylquinolin-4-amine;andtrans-4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}pyrrolidin-3-ol.32. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:trans-4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}pyrrolidin-3-ol;cis-4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}pyrrolidin-3-ol;N-[trans-4-fluoropyrrolidin-3-yl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;4-[(3-aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-ol;2-({4-[(3-aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}oxy)ethanol;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(2-methoxyethoxy)quinolin-4-yl]propane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(pyridin-2-yloxy)quinolin-4-yl]propane-1,3-diamine;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol;3-{[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}propane-1,2-diol;and3-{[2-(8-chloro-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol.33. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:3-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}propane-1,2-diol;3-{[6-methyl-2-(5-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]amino}propane-1,2-diol;N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-[7-(morpholin-4-yl)-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-2-{1,1-dioxido-7-[4-(propan-2-yl)piperazin-1-yl]-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl}-6-methylquinolin-4-amine;3-{[4-(4-aminoquinolin-2-yl)-1,1-dioxido-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl]oxy}propan-1-ol;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-8-phenoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N˜3˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninamide;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}butanamide;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropanamide;andN˜2˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-L-alaninamide.34. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N˜2˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycinamide;N˜2˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-methylglycinamide;(2S)-2-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol;(2R)-2-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-1-ol;N-[(2-amino-4,5-dihydro-1,3-oxazol-5-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[(2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-{[(4R)-2-amino-4,5-dihydro-1,3-oxazol-4-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-{[(4S)-2-amino-4,5-dihydro-1,3-oxazol-4-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;andcis-5-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-2-amine.35. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]glycinamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylalaninamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]alaninamide;2-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]butanamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methoxy-2-methylpropanamide;N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4,4-trifluorobutane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninamide;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-N-{[3-(ethylamino)oxetan-3-yl]methyl}-6-methylquinolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[1-(oxetan-3-yl)pyrrolidin-3-yl]quinolin-4-amine;andN′-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-ethyl-N-(oxetan-3-yl)ethane-1,2-diamine.36. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(oxetan-3-yl)propane-1,3-diamine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N-(oxetan-3-yl)pyrrolidin-3-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(oxetan-3-yl)ethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(pyridin-2-yl)ethane-1,2-diamine;(4R)-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-hydroxypyrrolidin-2-one;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-5-oxopyrrolidine-3-carboxamide;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(1H-pyrazol-3-yl)quinolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyridine-3-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]piperidine-2-carboxamide;andN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-(pyridin-2-yl)acetamide.37. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]methanesulfonamidetrifluoroacetate;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrazine-2-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-hydroxyacetamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyridine-2-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]azetidine-2-carboxamide;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-phenylurea;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-ethylurea;N-[6-cyclopropyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]propane-1,3-diamine;4-[(3-aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carbonitrile;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethenylquinolin-4-yl]propane-1,3-diamine;andN-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethynylquinolin-4-yl]propane-1,3-diamine.38. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-{[3-(benzylamino)oxetan-3-yl]methyl}-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;2-fluoro-N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane-1,3-diamine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;2,2-difluoro-N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane-1,3-diamine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2,2-difluoropropane-1,3-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-fluoropropane-1,3-diamine;N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]propane-1,3-diamine;N-[(3-aminooxetan-3-yl)methyl]-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;andN-[(3-aminooxetan-3-yl)methyl]-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine.39. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-[(3-aminooxetan-3-yl)methyl]-6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]amino}ethanol;2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-methylpropane-1,2-diamine;N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;N-[(1-aminocyclobutyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;andN-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine.40. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:(−)-N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinazolin-4-amine;(+)-N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-methyl-2-[1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl]quinazolin-4-amine;N˜4˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-fluorobutane-1,4-diamine;N˜1˜-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]-2-fluorobutane-1,4-diamine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;trans-4-fluoro-1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-amine;N-(Azetidin-3-yl)-6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-(2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}ethyl)acetamide;N-{[3-({[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}methyl)oxetan-3-yl]methyl}acetamide;andN-(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propyl)acetamide.41. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]acetamide;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-methylpyrrolidin-3-amine;N-[(3-aminooxetan-3-yl)methyl]-2-(9-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;4-(4-{[(3-aminooxetan-3-yl)methyl]amino}-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepin-7-ol1,1-dioxide;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropane-1,2-diol;4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}butane-1,3-diol;N-[6-methyl-2-(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(2-methyl-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-4-amine;N-[(3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}oxetan-3-yl)methyl]-2,2,2-trifluoroacetamide;N-[3-(aminomethyl)oxetan-3-yl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;and2-(aminomethyl)-2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propane-1,3-diol.42. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:4-amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-2-one;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(methylsulfinyl)ethyl]quinolin-4-amine;N-{2-[(2-aminoethyl)sulfonyl]ethyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine;N-[2-(1-imino-1-oxido-1,2,3,5-tetrahydro-4H-1lambda˜4˜,4-benzothiazepin-4-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(S-methylsulfonimidoyl)ethyl]quinolin-4-amine;trans-4-amino-1-[2-(1-imino-1-oxido-1,2,3,5-tetrahydro-4H-1lambda˜4˜,4-benzothiazepin-4-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol;trans-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4-fluoropyrrolidin-3-amine;1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3-carboxamide;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-(methylsulfinyl)quinolin-4-yl]propane-1,3-diamine;4-[(3-aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxamide;and1-{4-[(3-aminopropyl)amino]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl}ethanol.43. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propanenitrile;2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(1H-tetrazol-5-yl)ethyl]quinolin-4-amine;N˜4˜-(2-aminoethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-4,6-diamine;5-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-oxa-5,7-diazaspiro[3.4]octan-6-one;3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]amino}propane-1,2-diol;3-{[6-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}propane-1,2-diol;N-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]ethane-1,2-diamine;N-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]ethane-1,2-diamine;N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]ethane-1,2-diamine;andN-[3-(aminomethyl)oxetan-3-yl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine.44. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-(trans-4-fluoropyrrolidin-3-yl)-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;N-(trans-4-fluoropyrrolidin-3-yl)-6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;1-[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]pyrrolidin-3-amine;N-(azetidin-3-yl)-6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;(4R)-4-{2-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethyl}-4,5-dihydro-1,3-oxazol-2-amine;3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoicacid;3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propan-1-amine;2-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]oxy}ethanamine;4-[6-methyl-4-(pyrrolidin-3-yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;4-[6-methyl-4-(piperidin-4-yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;4-(4,6-dimethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide; and[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](piperidin-4-yl)methanone.45. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:4-[6-methyl-4-(1H-pyrazol-3-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;4-[6-methyl-4-(phenylsulfonyl)quinolin-2-yl]-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide;N-(2-aminoethyl)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinoline-4-sulfonamide;methyl4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate;4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylicacid;[4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-6-(˜2˜H_3_)methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-amine;4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylicacid;4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylicacid;[4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol;[4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-6-yl]methanol;N-[(1-aminocyclopropyl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine;and2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-(pyrrolidin-3-yl)quinazolin-4-amine.46. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, wherein R¹ is hydrogen or halogen; R² and R⁴ are hydrogen;R³ is hydrogen or halogen; R⁵ is hydrogen or halogen; R⁶ is hydrogen,halogen, hydroxy, C₁₋₆alkoxy or carboxy; R⁷ is hydrogen, halogen,C₁₋₆alkoxy, C₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl orC₁₋₆alkylsulfonyl; R⁸ is hydrogen or halogen; R⁹ is hydrogen or ═O; R¹⁰is hydrogen or ═O, provided that R⁹ and R¹⁰ are not ═O simultaneously; Ais —C—R¹¹, wherein R¹¹ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy,trifluoromethyl, trifluoromethoxy, pyridinyloxy, difluoromethoxy orC₁₋₆alkylsulfonyl; X is —CH₂—, —O—, —NH—, —CF₂, —C(CH₃)(OH)—, C═O, or—C(═N—C₁₋₆alkoxy)-; Y is —CH— or nitrogen; Q is hydrogen; halogen;C₁₋₆alkyl, once or twice substituted by hydroxy provided thatdisubstitution of hydroxy is not on the same carbon;amino(CH₂)₂₋₆aminosulfonyl; 2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl; orNR¹²R¹³, wherein one of R¹² and R¹³ is hydrogen, C₁₋₆alkyl orhydroxy(CH₂)₂₋, and the other one is guanidino(CH₂)₂₋₆;3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;3-amino-1,1-dioxidothietan-3-ylmethyl;3-(aminomethyl)thietan-3-ylmethyl; amino(CH₂)₂₋₆—O—(CH₂)₂₋₆;amino(CH₂)₂₋₁₀; amino(CH₂)₁₋₆carbonyl;amino(CH₂)₁₋₆difluoromethyl(CH₂)₁₋₆; amino(CH₂)₁₋₆oxetanyl(CH₂)₁₋₆;amino(CH₂)₂₋₆sulfonyl(CH₂)₂₋₆; 3-aminocyclohexyl; 4-aminocyclohexyl;2-amino-4,5-dihydro-oxazol-5-yl(CH₂)₁₋₆; aminooxetanyl(CH₂)₁₋₆;C₁₋₆alkylamino(CH₂)₂₋₆; C₁₋₆alkylaminocarbonyl;diC₁₋₆alkylamino(CH₂)₂₋₆; hydroxy(CH₂)₂₋₆; piperazinyl(CH₂)₂₋₆;pyrrolidin-3-yl; or

 wherein R¹⁴ is hydrogen, C₁₋₆alkyl or hydroxy(CH₂)₁₋₆; R¹⁵ is hydroxy,hydroxy(CH₂)₁₋₆ or amino; and R¹⁶ is C₁₋₆alkyl, hydroxy(CH₂)₁₋₆ oramino(CH₂)₁₋₆; or R¹² and R¹³, with the nitrogen atom to which they areattached, may form a pyrrolidinyl, piperazinyl or diazepanyl ring; whichmay be unsubstituted, once or twice substituted by a group selected fromC₁₋₆alkyl, amino or hydroxy.
 47. The compound according to claim 46 or apharmaceutically acceptable salt thereof, wherein R¹ is hydrogen orchloro; R² and R⁴ are hydrogen; R³ is hydrogen or chloro; R⁵ is hydrogenor fluoro; R⁶ is hydrogen, fluoro, hydroxy, methoxy, ethoxy or carboxy;R⁷ is hydrogen, fluoro, bromo, methoxy, dimethylaminocarbonyl,methylsulfonyl or ethylsulfonyl; R⁸ is hydrogen or chloro; A is CR¹¹,wherein R¹¹ is hydrogen, fluoro, chloro, bromo, methyl, methoxy,trifluoromethyl, trifluoromethoxy, pyridinyloxy, difluoromethoxy ormethylsulfonyl; Q is hydrogen; chloro; hydroxymethyl;hydroxymethyl(hydroxy)ethyl; aminoethylaminosulfonyl;2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl; or NR¹²R¹³, wherein one of R¹²and R¹³ is hydrogen, methyl or hydroxyethyl; and the other one isaminobutyl; 3-aminocyclohexyl; 4-aminocyclohexyl;2-amino-4,5-dihydro-oxazol-5-ylmethyl;3-amino-1,1-dioxidothietan-3-ylmethyl; aminoethoxyethyl; aminoethyl;aminoethylsulfonylethyl; aminomethylcarbonyl;aminomethyldifluoromethylmethyl;3-aminomethyl-1,1-dioxidothietan-3-ylmethyl;3-(aminomethyl)thietan-3-ylmethyl; aminomethyloxetanylmethyl;aminooxetanylmethyl; aminopropyl; dimethylaminoethyl;ethylaminocarbonyl; guanidinoethyl; hydroxyethyl; hydroxypropyl;methylaminoethyl; piperazin-1-ylethyl; pyrrolidin-3-yl; or

 wherein R¹⁴ is hydrogen, methyl or hydroxymethyl; R¹⁵ is hydroxy,hydroxymethyl or amino; and R¹⁶ is methyl, hydroxymethyl or aminomethyl;or R¹² and R¹³, with the nitrogen atom to which they are attached, mayform a pyrrolidinyl, piperazinyl or diazepanyl ring; which may beunsubstituted, once or twice substituted by a group selected frommethyl, amino or hydroxy.
 48. The compound according to claim 46 or apharmaceutically acceptable salt thereof, selected from the groupconsisting of: N-[(3-aminooxetan-3-yl)methyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine;N-[2-(2-aminoethoxy)ethyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-N′-methylethane-1,2-diamine;1-amino-3-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}propan-2-ol;3-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}propane-1,2-diol;3-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}propan-1-ol;2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methyl-N-[2-(piperazin-1-yl)ethyl]quinolin-4-amine;N˜1˜-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]propane-1,2-diamine;cis-N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]cyclohexane-1,4-diamine;and2-(9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)-6-methyl-N-(pyrrolidin-3-yl)quinolin-4-amine.49. The compound according to claim 46 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:2,2′-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]imino}diethanol;N˜1˜-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-2-methylpropane-1,2-diamine;5,5-difluoro-2-[6-methyl-4-(4-methylpiperazin-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine;1-[2-(9,9-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)-6-methylquinolin-4-yl]-3-ethylurea;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine;5,5-difluoro-2-[6-methyl-4-(piperazin-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine;2-[4-(1,4-diazepan-1-yl)-6-methylquinolin-2-yl]-5,5-difluoro-2,3,4,5-tetrahydro-1H-2-benzazepine;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-N-methylethane-1,2-diamine;1-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]pyrrolidin-3-amine;2-{[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]amino}ethanol;andN-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine.50. The compound according to claim 46 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]cyclohexane-1,3-diamine;N′-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]-N,N-dimethylethane-1,2-diamine;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]propane-1,3-diamine;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]butane-1,4-diamine;trans-4-amino-1-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol;N-{[3-(aminomethyl)-1,1-dioxidothietan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine;N-{2-[(2-aminoethyl)sulfonyl]ethyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-amine;N-{[3-(aminomethyl)thietan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine;N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine;and2-(aminomethyl)-2-({[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-yl]amino}methyl)propane-1,3-diol.51. The compound according to claim 46, or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:2-(4-{[(3-aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-ol;N-[(3-aminooxetan-3-yl)methyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine;N-[(3-amino-1,1-dioxidothietan-3-yl)methyl]-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine;N-[2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-yl]-2,2-difluoropropane-1,3-diamine;N-[2-(7-bromo-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-chloroquinolin-4-yl]ethane-1,2-diamine;2-{4-[(2-aminoethyl)amino]quinolin-2-yl}-2,3,4,5-tetrahydro-1H-2-benzazepin-8-ol;N-[6-methyl-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(8-fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine;N-[6-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[6-chloro-2-(9-fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(8-fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;and1-amino-3-{[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-oltrifluoroacetate.
 52. The compound according to claim 46 or apharmaceutically acceptable salt thereof, selected from the groupconsisting of:N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[6-bromo-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[6-methoxy-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(6-chloro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(7-fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine;N-methyl-N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(7-methoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(7-fluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4yl]ethane-1,2-diamine;N-[2-(8-methoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[6-(difluoromethoxy)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-(trifluoromethyl)quinolin-4-yl]ethane-1,2-diamine;andN-[8-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine.53. The compound according to claim 46 or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:N-[6-fluoro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N,N-dimethyl-N′-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-(trifluoromethoxy)quinolin-4-yl]ethane-1,2-diamine;N-[6-(methylsulfonyl)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;2-{4-[(2-aminoethyl)amino]quinolin-2-yl}-2,3,4,5-tetrahydro-1H-2-benzazepine-8-carboxylicacid; 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine;N-[5-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-{2-[7-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]quinolin-4yl}ethane-1,2-diamine;N-{2-[7-(ethylsulfonyl)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]quinolin-4-yl}ethane-1,2-diamine;N-[2-(8-ethoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;N-[6-(pyridin-2-yloxy)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethane-1,2-diamine;2-{4-[(2-aminoethyl)amino]-6-chloroquinolin-2-yl}-N,N-dimethyl-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxamide;2-{4-[(2-aminoethyl)amino]quinolin-2-yl}-7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;and1-(2-{[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}ethyl)guanidinetrifluoroacetate.
 54. The compound according to claim 46 or apharmaceutically acceptable salt thereof, selected from the groupconsisting of:N-[(2-amino-4,5-dihydro-1,3-oxazol-5-yl)methyl]-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-aminetrifluoroacetate;N-[(2-amino-4,5-dihydro-1,3-oxazol-5-yl)methyl]-6-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine;N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]glycinamide;3-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propan-1-amine;[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]methanol;2-(6-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine;3-[6-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propane-1,2-diol;(4S)-4-{2-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethyl}-4,5-dihydro-1,3-oxazol-2-amine;N-(2-aminoethyl)-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinoline-4-sulfonamidetrifluoroacetate;4-{4-[(2-aminoethyl)amino]-6-methylquinolin-2-yl}-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one;N-[6-methyl-2-(1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl)quinolin-4-yl]ethane-1,2-diamine;N-[2-(2,3-dihydro-1,4-benzoxazepin-4(5H)-yl)quinolin-4-yl]ethane-1,2-diamine;N-[(3-aminooxetan-3-yl)methyl]-2-[(5E)-5-(methoxyimino)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]-6-methylquinolin-4-amineand2-(4-{[(3-aminooxetan-3-yl)methyl]amino}-6-methylquinazolin-2-yl)-1,2,3,4-tetrahydro-5H-2-benzazepin-5-one.55. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound in accordance with claim 1 and a pharmaceuticallyacceptable carrier.
 56. A method for the treatment of respiratorysyncytial virus infection, which method comprisis administering aneffective amount of a compound of claim
 1. 57. A compound, wherein saidcompound isN-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine,or a pharmaceutically acceptable salt thereof.
 58. A pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundaccording to claim 57, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.
 59. A method for thetreatment of respiratory syncytial virus infection, comprising the stepof administering an effective amount of a compound according to claim57, or a pharmaceutically acceptable salt thereof.